Substituted 4-amino-pyrrolotriazine derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis

ABSTRACT

This invention relates to novel pyrrozolotriazine compounds, pharmaceutical compositions containing such compounds and the use of those compounds and compositions for the prevention and/or treatment of hyper-proliferative disorders and diseases associated with angiogenesis.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.12/085,879, filed May 30, 2008, now U.S. Pat. No. 8,133,995, which is aU.S. National stage application pursuant to 35 U.S.C. §371 ofInternational Application No. PCT/US2006/045996, filed Nov. 30, 2006,which claims the benefit of priority of U.S. Provisional PatentApplication No. 60/742,151, filed Dec. 2, 2005, the disclosures of eachof which are expressly incorporated herein by reference in theirentireties.

FIELD OF THE INVENTION

This invention relates to novel pyrrozolotriazine compounds,pharmaceutical compositions containing such compounds and the use ofthose compounds or compositions for treating hyper-proliferative and/orangiogenesis disorders, as a sole agent or in combination with otheractive ingredients.

BACKGROUND OF THE INVENTION

Cancer is a disease resulting from an abnormal growth of tissue. Certaincancers have the potential to invade into local tissues and alsometastasize to distant organs. This disease can develop in a widevariety of different organs, tissues and cell types. Therefore, the team“cancer” refers to a collection of over a thousand different diseases.

Over 4.4 million people worldwide were diagnosed with breast, colon,ovarian, lung, or prostate cancer in 2002 and over 2.5 million peopledied of these devastating diseases (Globocan 2002 Report). In the UnitedStates alone, over 1.25 million new cases and over 500,000 deaths fromcancer were predicted in 2005. The majority of these new cases wereexpected to be cancers of the colon (˜100,000), lung (˜170,000), breast(˜210,000) and prostate (˜230,000). Both the incidence and prevalence ofcancer is predicted to increase by approximately 15% over the next tenyears, reflecting an average growth rate of 1.4% (American CancerSociety, Cancer Facts and Figures 2005).

Cancer treatments are of two major types, either curative or palliative.The main curative therapies for cancer are surgery and radiation. Theseoptions are generally successful only if the cancer is found at an earlylocalized stage (Gibbs J B, 2000). Once the disease has progressed tolocally advanced cancer or metastatic cancer, these therapies are lesseffective and the goal of therapy aims at symptom palliation andmaintaining good quality of life. The most prevalent treatment protocolsin either treatment mode involve a combination of surgery, radiationtherapy and/or chemotherapy.

Cytotoxic drugs (also known as cytoreductive agents) are used in thetreatment of cancer, either as a curative treatment or with the aim ofprolonging life or palliating symptoms. Cytotoxics may be combined withradiotherapy and/or surgery, as neo-adjuvant treatment (initialchemotherapy aimed at shrinking the tumor, thereby rendering localtherapy such as surgery and radiation more effective) or as adjuvantchemotherapy (used in conjunction or after surgery and/or localizedtherapy). Combinations of different drugs are frequently more effectivethan single drugs: they may provide an advantage in certain tumors ofenhanced response, reduced development of drug resistance and/orincreased survival. It is for these reasons that the use of combinedcytotoxic regimens in the treatment of many cancers is very common.

Cytotoxic agents in current use employ different mechanisms to blockproliferation and induce cell death. They can be generally categorizedinto the following groups based on their mechanism of action: themicrotubule modulators that interfere with the polymerization ordepolymerization of microtubules (e.g. docetaxel, paclitaxel,vinblastine, vinorelbine); anti-metabolites including nucleoside analogsand other inhibitors of key cellular metabolic pathways (e.g.capecitabine, gemcitabine, methotrexate); agents that interact directlywith DNA (e.g. carboplatin, cyclophosphamide); anthracycline DNAinterchalators that interfere with DNA polymerase and Topoisomerase II(e.g. doxorubicin, epirubicin); and the non-anthracycline inhibitors ofTopoisomerase II and I enzymatic activity (e.g. topotecan, irinotecan,and etoposide). Even though different cytotoxic drugs act via differentmechanisms of action, each generally leads to at least transientshrinkage of tumors.

Cytotoxic agents continue to represent an important component in anoncologist's arsenal of weapons for use in fighting cancer. The majorityof drugs currently undergoing late Phase II and Phase III clinicaltrials are focusing on known mechanisms of action (tubulin bindingagents, anti-metabolites, DNA processing), and on incrementalimprovements in known drug classes (for example the taxanes or thecamptothecins). A small number of cytotoxic drugs based on novelmechanisms have recently emerged. Modes of action for these cytotoxicsinclude inhibition of enzymes involved in DNA modification [e.g. histonedeacetylase (HDAC)], inhibition of proteins involved in microtubulemovement and cell cycle progression (e.g. kinesins, aurora kinase), andnovel inducers of the apoptotic pathway (e.g. bcl-2 inhibitors).

The link between activity in tumor cell proliferation assays in vitroand anti-tumor activity in the clinical setting has been wellestablished in the art. For example, the therapeutic utility of taxol(Silvestrini et al. Stem Cells 1993, 11 (6), 528-35), taxotere (Bisseryet al. Anti Cancer Drugs 1995, 6 (3), 339), and topoisomerase inhibitors(Edelman et al. Cancer Chemother.

Cells protect their DNA by adopting a higher-order complex termedchromatin. Chromatin condensation is evident during mitosis and celldeath induced by apoptosis while chromatin decondensation is necessaryfor replication, repair, recombination and transcription. Histones areamong some of the DNA-binding proteins that are involved in theregulation of DNA condensation; and post-translational modifications ofhistone tails serve a critical role in the dynamiccondensation/decondensation that occurs during the cell cycle.Phoshorylation of the tails of histone H3 is involved in bothtranscription and cell division (Prigent et al. J. Cell Science 2003,116, 3677). A number of protein kinases have been reported tophosphorylate histone H3 and these kinases function both as signaltransduction and mitotic kinases.

Even though cytotoxic agents remain in the forefront of approaches totreat patients with advanced solid tumors, their limited efficacy andnarrow therapeutic indices result in significant side effects. Moreover,basic research into cancer has led to the investigation of less toxictherapies based on the specific mechanisms central to tumor progression.Such studies could lead to effective therapy with improvement of thequality of life for cancer patients. Thus, a new class of therapeuticagents has emerged, referred to as cytostatics. Cytostatics direct theiraction on tumor stabilization and are generally associated with a morelimited and less aggravating side effect profile. Their development hasresulted from the identification of specific genetic changes involved incancer progression and an understanding of the proteins activated incancer such as tyrosine kinases and serine/threonine kinases.

In addition to direct inhibition of tumor cell targets, cytostatic drugsare being developed to block the process of tumor angiogenesis. Thisprocess supplies the tumor with existing and new blood vessels tosupport continued nourishment and therefore help promote tumor growth.Key tyrosine kinase receptors including Vascular Endothelial GrowthFactor Receptor 2 (VEGFR2), Fibroblast Growth Factor 1 (FGFR1) and Tie2have been shown to regulate angiogenesis and have emerged as highlyattractive drug targets.

To support progressive tumor growth beyond the size of 1-2 mm³, it isrecognized that tumor cells require a functional stroma, a supportstructure consisting of fibroblast, smooth muscle cells, endothelialcells, extracellular matrix proteins, and soluble factors (Folkman, J.,Semin Oncol, 2002. 29 (6 Suppl 16), 15-8). Tumors induce the formationof stromal tissues through the secretion of soluble growth factors suchas PDGF and transforming growth factor-beta (TGF-beta), which in turnstimulate the secretion of complimentary factors by host cells such asfibroblast growth factor (FGF), epidermal growth factor (EGF), andvascular endothelial growth factor (VEGF). These stimulatory factorsinduce the formation of new blood vessels, or angiogenesis, which bringsoxygen and nutrients to the tumor and allows it to grow and provides aroute for metastasis. It is believed some therapies directed atinhibiting stroma formation will inhibit the growth of epithelial tumorsfrom a wide variety of histological types. (George, D. Semin Oncol,2001. 28 (5 Suppl 17), 27-33; Shaheen, R. M., et al., Cancer Res, 2001.61 (4), 1464-8; Shaheen, R. M., et al. Cancer Res, 1999. 59 (21),5412-6). However, because of the complex nature and the multiple growthfactors involved in angiogenesis process and tumor progression, an agenttargeting a single pathway may have limited efficacy. It is desirable toprovide treatment against a number of key signaling pathways utilized bytumors to induce angiogenesis in the host stroma. These include PDGF, apotent stimulator of stroma formation (Ostman, A. and C. H. Heldin, AdvCancer Res, 2001, 80, 1-38), FGF, a chemo-attractant and mitogen forfibroblasts and endothelial cells, and VEGF, a potent regulator ofvascularization. A major regulator of angiogenesis and vasculogenesis inboth embryonic development and some angiogenic-dependent diseases isvascular endothelial growth factor (VEGF; also called vascularpermeability factor, VPF). VEGF represents a family of isoforms ofmitogens existing in homodimeric forms due to alternative RNA splicing.The VEGF isoforms are reported to be highly specific for vascularendothelial cells (for reviews, see: Farrara et al. Endocr. Rev. 1992,13, 18; Neufield et al. FASEB J. 1999, 13, 9). VEGF expression isreported to be induced by hypoxia (Shweiki et al. Nature 1992, 359,843), as well as by a variety of cytokines and growth factors, such asinterleukin-1, interleukin-6, epidermal growth factor and transforminggrowth factor. To date, VEGF and the VEGF family members have beenreported to bind to one or more of three transmembrane receptor tyrosinekinases (Mustonen et al. J. Cell Biol., 1995, 129, 895), VEGF receptor-1(also known as flt-1 (fms-like tyrosine kinase-1)), VEGFR-2 (also knownas kinase insert domain containing receptor (KDR); the murine analogueof KDR is known as fetal liver kinase-1 (flk-1)), and VEGFR-3 (alsoknown as flt-4). KDR and flt-1 have been shown to have different signaltransduction properties (Waltenberger et al. J. Biol. Chem. 1994, 269,26988); Park et al. Oncogene 1995, 10, 135). Thus, KDR undergoes strongligand-dependant tyrosine phosphorylation in intact cells, whereas flt-1displays a weak response. Thus, binding to KDR is believed to be acritical requirement for induction of the full spectrum of VEGF-mediatedbiological responses.

In vivo, VEGF plays a central role in vasculogenesis, and inducesangiogenesis and permeabilization of blood vessels. Deregulated VEGFexpression contributes to the development of a number of diseases thatare characterized by abnormal angiogenesis and/or hyperpermeabilityprocesses. It is believed regulation of the VEGF-mediated signaltransduction cascade by some agents can provide a useful mode forcontrol of abnormal angiogenesis and/or hyperpermeability processes.

The vascular endothelial growth factors (VEGF, VEGF-C, VEGF-D) and theirreceptors (VEGFR2, VEGFR3) are not only key regulators of tumorangiogenesis, but also lymphangiogenesis. VEGF, VEGF-C and VEGF-D areexpressed in most tumors, primarily during periods of tumor growth and,often at substantially increased levels. VEGF expression is stimulatedby hypoxia, cytokines, oncogenes such as ras, or by inactivation oftumor suppressor genes (McMahon, G. Oncologist 2000, 5 (Suppl. 1), 3-10;McDonald, N. Q.; Hendrickson, W. A. Cell 1993, 73, 421-424).

The biological activities of the VEGFs are mediated through binding totheir receptors. VEGFR3 (also called Flt-4) is predominantly expressedon lymphatic endothelium in normal adult tissues. VEGFR3 function isneeded for new lymphatic vessel formation, but not for maintenance ofthe pre-existing lymphatics. VEGFR3 is also upregulated on blood vesselendothelium in tumors. Recently VEGF-C and VEGF-D, ligands for VEGFR3,have been identified as regulators of lymphangiogenesis in mammals.Lymphangiogenesis induced by tumor-associated lymphangiogenic factorscould promote the growth of new vessels into the tumor, providing tumorcells access to systemic circulation. Cells that invade the lymphaticscould find their way into the bloodstream via the thoracic duct. Tumorexpression studies have allowed a direct comparison of VEGF-C, VEGF-Dand VEGFR3 expression with clinicopathological factors that relatedirectly to the ability of primary tumors to spread (e.g., lymph nodeinvolvement, lymphatic invasion, secondary metastases, and disease-freesurvival). In many instances, these studies demonstrate a statisticalcorrelation between the expression of lymphangiogenic factors and theability of a primary solid tumor to metastasize (Skobe, M. et al. NatureMed. 2001, 7 (2), 192-198; Stacker, S. A. et al. Nature Med. 2001, 7(2), 186-191; Makinen, T. et al. Nature Med. 2001, 7 (2), 199-205;Mandriota, S. J. et al. EMBO J. 2001, 20 (4), 672-82; Karpanen, T. etal. Cancer Res. 2001, 61 (5), 1786-90; Kubo, H. et al. Blood 2000, 96(2), 546-53).

Hypoxia appears to be an important stimulus for VEGF production inmalignant cells. Activation of p38 MAP kinase is required for VEGFinduction by tumor cells in response to hypoxia (Blaschke, F. et al.Biochem. Biophys. Res. Commun. 2002, 296, 890-896; Shemirani, B. et al.Oral Oncology 2002, 38, 251-257). In addition to its involvement inangiogenesis through regulation of VEGF secretion, p38 MAP kinasepromotes malignant cell invasion, and migration of different tumor typesthrough regulation of collagenase activity and urokinase plasminogenactivator expression (Laferriere, J. et al. J. Biol. Chem. 2001, 276,33762-33772; Westermarck, J. et al. Cancer Res. 2000, 60, 7156-7162;Huang, S. et al. J. Biol. Chem. 2000, 275, 12266-12272; Simon, C. et al.Exp. Cell Res. 2001, 271, 344-355). Moreover, VEGF activates theextracellular signal-regulated protein kinase (ERK) in human umbilicalvein endothelial cells (HUVEC) (Yu, Y.; Sato, D. J. Cell Physiol 1999,178, 235-246).

The VEGF-VEGFR2 signaling pathway has been extensively characterized asan important regulator of angiogenesis. Mice lacking VEGFR2 (Flk-1) arealmost completely lacking in vasculature and have very few endothelialcells (Shalaby et al., Nature, 1995, 376, 62-66). VEGF is a potentmitogen for endothelial cells, promotes angiogenic sprouting, andincreases vascular permeability (reviewed in Yancopoulos et al. Nature2000, 407, 242). Administration of soluble VEGFR2 inhibits the growth ofwide variety of tumors (Shirakawa et al. Int J Cancer, 2002, 99, 244,Bruns et al. Cancer, 2000, 89, 495, Millauer et al., Nature 1994, 367,576). Similarly, neutralizing antibodies to VEGF (Kim et al., Nature,1993, 262, 841) or VEGFR2 (Prewett et al., Cancer Res 1999, 59, 5209),as well as VEGF antisense (Saleh et al. Cancer Res 1996, 56, 393)suppress tumor growth in vivo. Furthermore, small molecule inhibitors ofVEGFR2 have been shown to inhibit tumor growth in preclinical xenograftmodels (reviewed in Shepherd and Sridhar, Lung Cancer, 2003, 41, S63)and are being tested in clinical trials. A monoclonal antibody to VEGF(Avastin™) was recently approved for use in combination with otheranticancer drugs for treatment of advanced colon cancer.

The Ang-Tie2 signal transduction pathway also plays a key role invascular formation, particularly with respect to remodeling andstabilization of vessels. The major ligands for Tie2, Angiopoietin-1 andAngiopoietin-2 (Ang1 and Ang2), have distinct activities. While Ang1 isa Tie2 agonist, promoting vessel maturation and stability, Ang2 ispartial Tie2 agonist/antagonist having varied activities that aredependent on the tissue and growth factor context (Yancopoulos et al.Nature, 2000, 407, 242). When the local concentration of VEGF is low,Ang2 promotes vessel regression, whereas in areas where VEGFconcentrations are high, Ang2 induces vessel destabilization andbranching (Holash et al. Ocogene, 1999, 18, 5356). This latter situationis likely the case during active tumor angiogenesis. Ang1 has been shownto regulate endothelial cell survival (Kwak et al. FEBS, 1999, 448, 249,Bussolati et al. FEBS, 2003, 9, 1159) and migration (Witzenbichler etal. J. Biol Chem, 1998, 373, 18514). The role of Ang-Tie2 signaling intumor angiogenesis is supported by numerous xenograft tumor studiesinvolving the administration of soluble Tie2. Significant inhibition oftumor growth by soluble Tie2 was observed in the WIBC-9 and MC-5 humanbreast tumors (Shirakawa et al. Int J Cancer, 2002, 99, 344), C26 colonand TS/A breast tumors, R3230AC breast tumor (Lin et al. J Clin Invest,1997, 100, 2072), A375v melanoma (Siemeister et al. Cancer Res, 1999,59, 3185), as well as 4T1 murine mammary and B16F10.9 murine melanomatumors.

The central role of the FGF-FGFR1 signal transduction pathway inangiogenesis is well established. The FGF family includes 22 membersexpressed from different genes and having distinct activities (Ornitzand Itoh, Genome Biology, 2001, 2, reviews 3005). During mammaliandevelopment, FGF1 and FGF2 regulate branching morphogenesis in tissuesundergoing vascularization. Administration of FGFs can promoteneovascularization in ischemic tissues (Yanagisawa-Miwa et al., Science,1992, 257, 1401, Tabata et al Cardiovasc Res, 1997, 35, 470). FGFR1binds FGF1 and FGF2 with similar affinity (Dionne et al., EMBO J, 1990,9, 2685). The FGF-FGFR1 pathway has also been associated withangiogenesis in a variety of tumor types. FGF2 is a key regulator ofangiogenesis in prostate cancer (Doll et al. Prostate, 2001, 49, 293)and melanomas (Straume and Akslen Am J Pathol, 2002, 160, 1009). Inaddition, antisense targeting of FGFR1 (Wang and Becker Nat Med, 1997,3, 887) or anti-FGF2 antibodies (Rofstad and Halsor Cancer Res, 2000,60, 4932) inhibit tumor growth and angiogenesis in human melanomas.Similarly, expression of soluble FGFR decreases the growth ofspontaneous pancreatic tumors in mice (Compagni et al. Cancer Res, 2000,60, 7163), as well as xenografted pancreatic tumors (Wagner et al.Gastroenterology, 1998, 114, 798). Overexpression and amplification ofthe FGFR1 gene in human breast tumors (Jacquemier et al. Int J Cancer,1994, 59, 373) and bladder cancers (Simon et al. Cancer Res, 2001, 61,4514), has been reported whereas translocation of FGFR1 resulting in anactivated chimeric kinase has been identified in myeloproliferativedisorders with lymphoma (Gausch et al. Mol Cell Biol 2001, 21, 8129) andChronic Myelogenous Leukemias (CML, Demiroglu et al., Blood, 2001, 98,3778).

The activation of FGFR1 by FGF induces both the MAPK/ERK and thePI3K/Akt pathways. In contrast to Ang1, which is not a mitogen, FGFstimulates cell proliferation via the MAPK/ERK pathway (Bikfalvi et al.,Endocr Rev, 1997, 18, 26). Activation of FGFR1 leads to the recruitmentof adaptor proteins FRS2 and GRB2, which recruit SOS to the plasmamembrane leading to the activation of RAS (Kouhara et al., Cell, 1997,89, 693). Activated RAS, which subsequently activates RAF, MEK, thenERK, leads to cell proliferation. The activation of p38 MAPK has alsobeen reported to be involved in FGF-induced cell proliferation (Maher, JBiol Chem, 1999, 274, 17491). The recruitment of GRB2 to activated FGFR1also recruits Gab1, which induces the PI3K/Akt pathway (Ong et al., MolCell Biol, 2000, 20, 979), and promotes cell survival. This effect ofAkt on cell survival is mediated, in part through mTOR and p70^(S6K)(Gausch et al., Mol Cell, Biol, 2001, 21, 8129). The effects of FGF oncell migration have been shown to be mediated, in part, by ERKactivation and c-Fes (reviewed in Javerzat et al., Trends in MolecularMedicine, 2002, 8, 483).

PDGF is another key regulator of stromal formation which is secreted bymany tumors in a paracrine fashion and is believed to promote the growthof fibroblasts, smooth muscle and endothelial cells, promoting stromaformation and angiogenesis. PDGF was originally identified as the v-sisoncogene product of the simian sarcoma virus (Heldin, C. H., et al., JCell Sci. Suppl, 1985, 3, 65-76). The growth factor is made up of twopeptide chains, referred to as A or B chains which share 60% homology intheir primary amino acid sequence. The chains are disulfide cross linkedto form the 30 kDa mature protein composed of either AA, BB or AB homo-or heterodimmers. PDGF is found at high levels in platelets, and isexpressed by endothelial cells and vascular smooth muscle cells. Inaddition, the production of PDGF is up regulated under low oxygenconditions such as those found in poorly vascularized tumor tissue(Kourembanas, S., et al., Kidney Int, 1997, 51 (2), 438-43). PDGF bindswith high affinity to the PDGF receptor, a 1106 amino acid 124 kDatransmembrane tyrosine kinase receptor (Heldin, C. H., A. Ostman, and L.Ronnstrand, Biochim Biophys Acta, 1998. 1378 (1), 79-113). PDGFR isfound as homo- or heterodimer chains which have 30% homology overall intheir amino acid sequence and 64% homology between their kinase domains(Heldin, C. H., et al. Embo J, 1988, 7(5), 1387-93). PDGFR is a memberof a family of tyrosine kinase receptors with split kinase domains thatincludes VEGFR2 (KDR), VEGFR3 (Flt4), c-Kit, and FLT3. The PDGF receptoris expressed primarily on fibroblast, smooth muscle cells, and pericytesand to a lesser extent on neurons, kidney mesangial, Leydig, and Schwanncells of the central nervous system. Upon binding to the receptor, PDGFinduces receptor dimerization and undergoes auto- andtrans-phosphorylation of tyrosine residues which increase the receptors'kinase activity and promotes the recruitment of downstream effectorsthrough the activation of SH2 protein binding domains. A number ofsignaling molecules form complexes with activated PDGFR includingPI-3-kinase, phospholipase C-gamma, src and GAP (GTPase activatingprotein for p21-ras) (Soskic, V., et al. Biochemistry, 1999, 38 (6),1757-64). Through the activation of PI-3-kinase, PDGF activates the Rhosignaling pathway inducing cell motility and migration, and through theactivation of GAP, induces mitogenesis through the activation of p21-rasand the MAPK signaling pathway.

In adults, it is believed the major function of PDGF is to facilitateand increase the rate of wound healing and to maintain blood vesselhomeostasis (Baker, E. A. and D. J. Leaper, Wound Repair Regen, 2000. 8(5), 392-8; Yu, J., A. Moon, and H. R. Kim, Biochem Biophys Res Commun,2001. 282 (3), 697-700). PDGF is found at high concentrations inplatelets and is a potent chemoattractant for fibroblast, smooth musclecells, neutrophils and macrophages. In addition to its role in woundhealing PDGF is known to help maintain vascular homeostasis. During thedevelopment of new blood vessels, PDGF recruits pericytes and smoothmuscle cells that are needed for the structural integrity of thevessels. PDGF is thought to play a similar role during tumorneovascularization. As part of its role in angiogenesis PDGF controlsinterstitial fluid pressure, regulating the permeability of vesselsthrough its regulation of the interaction between connective tissuecells and the extracellular matrix. Inhibiting PDGFR activity can lowerinterstitial pressure and facilitate the influx of cytotoxics intotumors improving the anti-tumor efficacy of these agents (Pietras, K.,et al. Cancer Res, 2002. 62 (19), 5476-84; Pietras, K., et al. CancerRes, 2001. 61 (7), 2929-34).

PDGF can promote tumor growth through either the paracrine or autocrinestimulation of PDGFR receptors on stromal cells or tumor cells directly,or through the amplification of the receptor or activation of thereceptor by recombination. Over expressed PDGF can transform humanmelanoma cells and keratinocytes (Forsberg, K., et al. Proc Natl AcadSci USA., 1993. 90 (2), 393-7; Skobe, M. and N. E. Fusenig, Proc NatlAcad Sci USA, 1998. 95 (3), 1050-5), two cell types that do not expressPDGF receptors, presumably by the direct effect of PDGF on stromaformation and induction of angiogenesis. This paracrine stimulation oftumor stroma is also observed in carcinomas of the colon, lung, breast,and prostate (Bhardwaj, B., et al. Clin Cancer Res, 1996, 2 (4), 773-82;Nakanishi, K., et al. Mod Pathol, 1997, 10 (4), 341-7; Sundberg, C., etal. Am J Pathol, 1997, 151 (2), 479-92; Lindmark, G., et al. Lab Invest,1993, 69 (6), 682-9; Vignaud, J. M., et al, Cancer Res, 1994, 54 (20),5455-63) where the tumors express PDGF, but not the receptor. Theautocrine stimulation of tumor cell growth, where a large faction oftumors analyzed express both the ligand PDGF and the receptor, has beenreported in glioblastomas (Fleming, T. P., et al. Cancer Res, 1992, 52(16), 4550-3), soft tissue sarcomas (Wang, J., M. D. Coltrera, and A. M.Gown, Cancer Res, 1994, 54 (2), 560-4) and cancers of the ovary(Henriksen, R., et al. Cancer Res, 1993, 53 (19), 4550-4), prostate(Fudge, K., C. Y. Wang, and M. E. Stearns, Mod Pathol, 1994, 7 (5),549-54), pancreas (Funa, K., et al. Cancer Res, 1990, 50 (3), 748-53)and lung (Antoniades, H. N., et al., Proc Natl Acad Sci USA, 1992, 89(9), 3942-6). Ligand independent activation of the receptor is found toa lesser extent but has been reported in chronic myelomonocytic leukemia(CMML) where the a chromosomal translocation event forms a fusionprotein between the Ets-like transcription factor TEL and the PDGFreceptor. In addition, activating mutations in PDGFR have been found ingastrointestinal stromal tumors in which c-Kit activation is notinvolved (Heinrich, M. C., et al., Science, 2003, 9, 9).

Certain PDGFR inhibitors will interfere with tumor stromal developmentand are believed to inhibit tumor growth and metastasis.

Several new drugs that are directed at various molecular targets havebeen approved over the past several years for the treatment of cancer.Imatinib is an inhibitor of the Abl tyrosine kinase and was the firstsmall molecule tyrosine kinase inhibitor to be approved for thetreatment of chronic myeloid leukemia (CML). Based on additionalactivity of imatinib against the receptor tyrosine kinase activated ingastrointestinal stromal tumors (GIST), c-KIT, it was subsequentlyapproved for the treatment of advanced GIST. Erlotinib, a small moleculeinhibitor of EGFR, was approved in late 2004 for the treatment ofnon-small cell lung carcinoma (NSCLC). Sorafenib, an inhibitor ofmultiple kinases including c-Raf and VEGFR2 was approved for thetreatment of advanced renal cell carcinoma (RCC) in December, 2005.Recently in January of 2006, Sunitinib, a multi-kinase inhibitor wasapproved for the treatment of refractory- or resistant-GIST and advancedRCC. These small molecule inhibitors demonstrate that targetedapproaches are successful for the treatment of different types ofcancers.

Despite advancements in the art, there remains a need for cancertreatments and anti-cancer compounds.

Compounds and compositions described herein, including salts,metabolites, solvates, solvates of salts, hydrates, prodrugs such asesters, polymorphs, and stereoisomeric forms thereof, exhibitanti-proliferative and anti-angiogenic activity and are thus useful toprevent or treat the disorders associated with hyper-proliferation andangiogenesis.

DESCRIPTION OF THE INVENTION

In embodiment one, the present invention provides a compound of formula(I)

-   -   wherein    -   R¹ represents        -   1.1) phenyl or a bicyclic carbocycle of 9-10 ring members,            in which at least one ring is aromatic, R¹ optionally            bearing up to 4 substituents independently selected from the            group consisting of            -   1.1.a) (C₁-C₄)alkyl, which may optionally bear up to 3                substituents independently selected from            -    1.1.a1) halogen;            -    1.1.a2) OR⁵ wherein R⁵ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or —(C₁-C₃)mono- or                di-alkylamino;            -    1.1.a3) —NR⁶R⁷ in which R⁶ and R⁷ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen or                OR^(7a) wherein R^(7a) represents H or (C₁-C₃)alkyl, or                R⁶ and R⁷ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁸ wherein R⁸ represents H or (C₁-C₃)alkyl;                and            -    1.1.a4) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N,            -   1.1.b) —(C₃-C₆)cycloalkyl which may optionally bear up                to 2 substituents independently selected from            -    1.1.b1) halogen; and            -    1.1.b2) OR⁹ wherein R⁹ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or (C₁-C₃)mono- or                di-alkylamino;            -   1.1.c) OR¹⁰ wherein            -    R¹⁰ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl; or                (C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -    1.1.c1) halogen;            -    1.1.c2) OR¹¹ wherein R¹¹ represents H or (C₁-C₃)alkyl                which may optionally bear (C₁-C₃)mono- or di-alkylamino;                and            -    1.1.c3) NR¹²R¹³ in which R¹² and R¹³ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R¹² and R¹³ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR¹⁴ wherein R¹⁴ represents H or (C₁-C₃)alkyl;            -   1.1.d) —C(O)—OR¹⁵ wherein R¹⁵ represents H or                —(C₁-C₄)alkyl which may optionally bear up to 3                halogens;            -   1.1.e) —C(O)—NR¹⁶R¹⁷ wherein            -    R¹⁶ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R¹⁷ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -    1.1.e1) halogen;            -    1.1.e2) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;            -    1.1.e3) phenyl;            -    1.1.e4) —SO₂CH₃;            -    1.1.e5) —OR¹⁸ wherein R¹⁸ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -    1.1.e6) —NR¹⁹R²⁰ in which R¹⁹ and R²⁰ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R¹⁹ and R²⁰ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR²¹ wherein R²¹ represents H or (C₁-C₃)alkyl;            -   1.1.f) —N(R²²)—C(O)—R²³ wherein            -    R²² represents H or (C₁-C₃)alkyl; and            -    R²³ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -    1.1.f1) optionally substituted phenyl,            -    1.1.f2) OR²⁴ wherein R²⁴ represents H or (C₁-C₃)alkyl,                or            -    1.1.f3) NR²⁵R²⁶ wherein R²⁵ and R²⁶ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen, or                R²⁵ and R²⁶ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR²⁷ wherein R²⁷ represents H or (C₁-C₃)alkyl;            -   1.1.g) —SO₂NR²⁸R²⁹ wherein            -    R²⁸ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R²⁹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with:            -    1.1.g1) halogen;            -    1.1.g2) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;            -    1.1.g3) phenyl;            -    1.1.g4) —SO₂CH₃;            -    1.1.g5) —OR³⁰ wherein R³⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -    1.1.g6) —NR³¹R³² in which R³¹ and R³² are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R³¹ and R³² may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR³³ wherein R³³ represents H or (C₁-C₃)alkyl;            -   1.1.h) —N(R³⁴)—SO₂—R³⁵ wherein            -    R³⁴ represents H or (C₁-C₃)alkyl, and            -    R³⁵ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -    1.1.h1) halogen;            -    1.1.h2) optionally substituted phenyl,            -    1.1.h3) OR³⁶ wherein R³⁶ represents H or (C₁-C₃)alkyl,                or            -    1.1.h4) NR³⁷R³⁸ wherein R³⁷ and R³⁸ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen, or                R³⁷ and R³⁸ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR³⁹ wherein R³⁹ represents H or (C₁-C₃)alkyl;            -   1.1.i) —NR⁴⁰R⁴¹ in which R⁴⁰ and R⁴¹ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen or                OR⁴² in which R⁴² represents H or (C₁-C₃)alkyl, or R⁴⁰                and R⁴¹ may be joined and taken together with the N atom                to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁴³ wherein R⁴³ represents H or (C₁-C₃)alkyl;            -   1.1.j) halogen;            -   1.1.k) optionally substituted phenyl;            -   1.1.l) NO₂;            -   1.1.m) CN; and            -   1.1.n) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;    -   or    -   R¹ represents        -   1.2) a 5-6 membered aromatic heterocycle containing up to 3            heteroatoms independently selected from the group consisting            of N, O, and S; or a bicyclic heterocycle of 8-10 ring            members in which at least one ring is aromatic and contains            up to 3 moieties independently selected from the group            consisting of N, N→O, O, and S, and any non-aromatic ring of            said bicyclic heterocycle optionally contains up to three            moieties independently selected from the group consisting of            O, S, S(O), S(O)₂, and NR⁴⁴ wherein R⁴⁴ represents H or            —(C₁-C₃)alkyl; said R¹ heterocycle optionally bearing up to            4 substituents independently selected from the group            consisting of            -   1.2.a) (C₁-C₄)alkyl, which may optionally bear up to 3                substituents independently selected from            -    1.2.a1) halogen;            -    1.2.a2) OR⁴⁵ wherein R⁴⁵ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or —(C₁-C₃)mono- or                di-alkylamino;            -    1.2.a3) —NR⁴⁶R⁴⁷ in which R⁴⁶ and R⁴⁷ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen or                OR^(47a) wherein R^(47a) represents H or (C₁-C₃)alkyl,                or R⁴⁶ and R⁴⁷ may be joined and taken together with the                N atom to which they are attached form a 5-6 membered                ring which may optionally contain a ring member selected                from O, S, and NR⁴⁸ wherein R⁴⁸ represents H or                (C₁-C₃)alkyl; and            -    1.2.a4) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;            -   1.2.b) —(C₃-C₆)cycloalkyl which may optionally bear up                to 2 substituents independently selected from            -    1.2.b1) halogen; and            -    1.2.b2) OR⁴⁹ wherein R⁴⁹ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or —(C₁-C₃)mono- or                di-alkylamino;            -   1.2.c) OR⁵⁰ wherein            -    R⁵⁰ represents H; phenyl; benzyl; —(C₃-C₆)cycloalkyl;                or —(C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -    1.2.c1) halogen;            -    1.2.c2) OR⁵¹ wherein R⁵¹ represents H or (C₁-C₃)alkyl                which may optionally bear —(C₁-C₃)mono- or                di-alkylamino; and            -    1.2.c3) —NR⁵²R⁵³ in which R⁵² and R⁵³ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁵² and R⁵³ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁵⁴ wherein R⁵⁴ represents H or (C₁-C₃)alkyl;            -   1.2.d) —C(O)—OR⁵⁵ wherein R⁵⁵ represents H or                —(C₁-C₄)alkyl which may optionally bear up to 3                halogens;            -   1.2.e) —C(O)—NR⁵⁶R⁵⁷ wherein            -    R⁵⁶ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R⁵⁷ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -    1.2.e1) halogen;            -    1.2.e2) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;            -    1.2.e3) phenyl;            -    1.2.e4) —SO₂CH₃;            -    1.2.e5) —OR⁵⁸ wherein R⁵⁸ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -    1.2.e6) —NR⁵⁹R⁶⁰ in which R⁵⁹ and R⁶⁰ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁵⁹ and R⁶⁰ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁶¹ wherein R⁶¹ represents H or (C₁-C₃)alkyl;            -   1.2.f) —N(R⁶²)—C(O)—R⁶³ wherein            -    R⁶² represents H or (C₁-C₃)alkyl; and            -    R⁶³ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -    1.2.f1) optionally substituted phenyl,            -    1.2.f2) OR⁶⁴ wherein R⁶⁴ represents H or (C₁-C₃)alkyl,                or            -    1.2.f3) NR⁶⁵R⁶⁶ wherein R⁶⁵ and R⁶⁶ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁶⁵ and R⁶⁶ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁶⁷ wherein R⁶⁷ represents H or (C₁-C₃)alkyl;            -   1.2.g) —SO₂NR⁶⁸R⁶⁹ wherein            -    R⁶⁸ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R⁶⁹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -    1.2.g1) halogen;            -    1.2.g2) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;            -    1.2.g3) phenyl;            -    1.2.g4) —SO₂CH₃;            -    1.2.g5) —OR⁷⁰ wherein R⁷⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -    1.2.g6 —NR⁷¹R⁷² in which R⁷¹ and R⁷² are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁷¹ and R⁷² may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁷³ wherein R⁷³ represents H or (C₁-C₃)alkyl;            -   1.2.h) —N(R⁷⁴)—SO₂—R⁷⁵ wherein            -    R⁷⁴ represents H or (C₁-C₃)alkyl, and            -    R⁷⁵ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -    1.2.h1) halogen;            -    1.2.h2) optionally substituted phenyl,            -    1.2.h3) OR⁷⁶ wherein R⁷⁶ represents H or (C₁-C₃)alkyl,                or            -    1.2.h4) NR⁷⁷R⁷⁸ wherein R⁷⁷ and R⁷⁸ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁷⁷ and R⁷⁸ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁷⁹ wherein R⁷⁹ represents H or (C₁-C₃)alkyl;            -   1.2.i) —NR⁸⁰R⁸¹ in which R⁸⁰ and R⁸¹ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen or                OR^(81a) wherein R^(81a) represents H or (C₁-C₃)alkyl,                or R⁸⁰ and R⁸¹ may be joined and taken together with the                N atom to which they are attached form a 5-6 membered                ring which may optionally contain a ring member selected                from O, S, and NR⁸² wherein R⁸² represents H or                (C₁-C₃)alkyl;            -   1.2.j) halogen;            -   1.2.k) optionally substituted phenyl;            -   1.2.l) NO₂;            -   1.2.m) CN; and            -   1.2.n) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;    -   R² represents halogen; —(C₁-C₅)alkyl which may optionally bear        halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen;    -   R³ represents        -   3.1) —(C₁-C₅)alkyl which is optionally substituted with            -   3.1.a) -halogen;            -   3.1.b) phenyl optionally substituted with halogen,                —(C₁-C₃)alkyl, or —(C₁-C₃)alkoxy,            -   3.1.c) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N, optionally                substituted with halogen or —(C₁-C₃)alkyl,            -   3.1.d) —CN,            -   3.1.e) —OR⁸³ wherein R⁸³ represents H or —(C₁-C₃)alkyl                which may optionally bear up to 3 substituents                independently selected from            -    3.1.e1) halogen;            -    3.1.e2) optionally substituted phenyl;            -    3.1.e3) —S(O)₂CH₃;            -    3.1.e4) OR⁸⁴ wherein R⁸⁴ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or —(C₁-C₃)mono- or                di-alkylamino; and            -    3.1.e5) —NR⁸⁵R⁸⁶ in which R⁸⁵ and R⁸⁶ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁸⁵ and R⁸⁶ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁸⁷ wherein R⁸⁷ represents H or (C₁-C₃)alkyl;            -   3.1.f) —(C₃-C₅)cycloalkyl which may optionally bear                halogen or OR⁸⁸ wherein R⁸⁸ represents H or                (C₁-C₃)alkyl; or            -   3.1.g) —NR⁸⁹R⁹⁰ wherein            -    R⁸⁹ represents H or —(C₁-C₃)alkyl which may optionally                bear halogen; and            -    R⁹⁰ represents H or —(C₁-C₄)alkyl which is optionally                substituted with                -   3.1.g1) halogen;                -   3.1.g2) a 5-6 membered heteroaromatic containing up                    to two heteroatoms selected from O, S, and N;                -   3.1.g3) phenyl;                -   3.1.g4) —SO₂CH₃;                -   3.1.g5) —OR⁹¹ wherein R⁹¹ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; or                -   3.1.g6) —NR⁹²R⁹³ in which R⁹² and R⁹³ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R⁹² and R⁹³ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR⁹⁴ wherein R⁹⁴ represents H or (C₁-C₃)alkyl;                    or                -   3.1.g7) R⁸⁹ and R⁹⁰ may be joined and taken together                    with the N to which they are attached form an                    aromatic or nonaromatic 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR⁹⁵ wherein R⁹⁵ represents H or (C₁-C₃)alkyl;        -   3.2)

wherein

-   -   -   -   R⁹⁶ represents            -   3.2.a) H,            -   3.2.b) —(C₃-C₅)cycloalkyl which may optionally bear                halogen or —(C₁-C₃)alkoxy; or            -   3.2.c) —(C₁-C₅)alkyl which may optionally bear up to 3                substituents independently selected from            -    3.2.c1) halogen;            -    3.2.c2) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;            -    3.2.c3) phenyl;            -    3.2.c4) —S(O)₂CH₃;            -    3.2.c5) —OR⁹⁷ wherein R⁹⁷ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or —(C₁-C₃)mono- or                di-alkylamino; and            -    3.2.c6) —NR⁹⁸R⁹⁹ in which R⁹⁸ and R⁹⁹ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen or                OR^(99a) wherein R^(99a) represents H or (C₁-C₃)alkyl,                or R⁹⁸ and R⁹⁹ may be joined and taken together with the                N atom to which they are attached form a 5-6 membered                ring which may optionally contain a ring member selected                from O, S, and NR¹⁰⁰ wherein R¹⁰⁰ represents H or                (C₁-C₃)alkyl;

        -   3.3)

wherein R¹⁰¹ represents H or —(C₁-C₅)alkyl which may optionally bear upto 3 substituents independently selected from

-   -   -   -   3.3.a) halogen; and            -   3.3.b) phenyl;

        -   3.4)

wherein

-   -   -   -   R¹⁰² represents H or —(C₁-C₃)alkyl which may optionally                bear halogen; and            -   R¹⁰³ represents H or —(C₁-C₅)alkyl which may optionally                bear up to 3 substituents independently selected from            -    3.4.a) halogen;            -    3.4.b) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;            -    3.4.c) phenyl;            -    3.4.d) —S(O)₂CH₃;            -    3.4.e) OR¹⁰⁴ wherein R¹⁰⁴ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; and            -    3.4.f) —NR¹⁰⁵R¹⁰⁶ in which R¹⁰⁵ and R¹⁰⁶ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁰⁵ and R¹⁰⁶ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁰⁷ wherein R¹⁰⁷                represents H or (C₁-C₃)alkyl;

        -   3.5) optionally substituted phenyl;

        -   3.6) a 5-6 membered heteroaromatic containing up to two            heteroatoms selected from O, S, and N;

        -   3.7) halogen;

        -   3.8) —CN; or

        -   3.9) —CH═N—OR¹⁰⁸ wherein R¹⁰⁸ represents H or            —C(O)—(C₁-C₃)alkyl;

    -   R⁴ represents        -   4.1) —(C₁-C₅)alkyl which is optionally substituted with            -   4.1.a) —(C₃-C₅)cycloalkyl which may optionally bear                halogen or OR¹⁰⁹ wherein R¹⁰⁹ represents H or                (C₁-C₃)alkyl;            -   4.1.b) -halogen;            -   4.1.c) —OR¹¹⁰ wherein R¹¹⁰ represents H or —(C₁-C₃)alkyl                which may optionally bear up to 3 substituents                independently selected from            -    4.1.c1) halogen;            -    4.1.c2) phenyl;            -    4.1.c3) —S(O)₂CH₃;            -    4.1.c4) OR¹¹¹ wherein R¹¹¹ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; and            -    4.1.c5) —NR¹¹²R¹¹³ in which R¹¹² and R¹¹³ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹¹² and R¹¹³ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹¹⁴ wherein R¹¹⁴                represents H or (C₁-C₃)alkyl;            -   4.1.d) —NR¹¹⁵R¹¹⁶ wherein            -    R¹¹⁵ represents H or —(C₁-C₃)alkyl which may optionally                bear halogen and            -    R¹¹⁶ represents H, optionally substituted phenyl, or                —(C₁-C₅)alkyl which may optionally bear up to 3                substituents independently selected from                -   4.1.d1) halogen;                -   4.1.d2) —S(O)₂CH₃;                -   4.1.d3) OR¹¹⁷ wherein R¹¹⁷ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; and                -   4.1.d4) —NR¹¹⁸R¹¹⁹ in which R¹¹⁸ and R¹¹⁹ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹¹⁸ and R¹¹⁹ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹²⁰ wherein R¹²⁰ represents H or (C₁-C₃)alkyl;            -   4.1.e) optionally substituted phenyl; or            -   4.1.f) a 5-6 membered aromatic heterocycle containing up                to two heteroatoms selected from O, S, and N;        -   4.2)

wherein R¹²¹ represents —(C₁-C₃)alkyl which may optionally bear halogenor —OR¹²² in which R¹²² represents H or —(C₁-C₃)alkyl;

-   -   -   -   d represents 1, 2, or 3;            -   e represents 0 or 1;            -   f represents 0, 1, or 2;

        -   4.3)

wherein R¹²³ represents —(C₁-C₃)alkyl which may optionally bear halogenor —OR¹²⁴ in which R¹²⁴ represents H or —(C₁-C₃)alkyl;

-   -   -   -   g represents 1, 2, or 3;            -   h represents 0, 1, or 2;

        -   4.4)

wherein

-   -   -   -   R¹²⁵ represents            -    4.4.a) H;            -    4.4.b) —(C₁-C₃)alkyl which may optionally bear halogen                or —OR¹²⁶ in which R¹²⁶ represents H or —(C₁-C₃)alkyl                which in turn is optionally substituted with halogen;            -    4.4.c) —SO₂R¹²⁷ wherein R¹²⁷ represents optionally                substituted phenyl, or —(C₁-C₃)alkyl which may                optionally bear halogen or OR¹²⁸ wherein R¹²⁸ represents                H or (C₁-C₃)alkyl;            -    4.4.d) —C(O)R¹²⁹ wherein                -   R¹²⁹ represents                -   4.4.d1) optionally substituted phenyl,                -   4.4.d2) —(C₁-C₃)alkyl which may optionally bear up                    to 3 substituents independently selected from                -    4.4.d2.1) halogen;                -    4.4.d2.2) optionally substituted phenyl;                -    4.4.d2.3) —S(O)₂CH₃;                -    4.4.d2.4) —OR¹³⁰ wherein R¹³⁰ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; and                -    4.4.d2.5) —NR¹³¹R¹³² in which R¹³¹ and 8132 are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹³¹ and R¹³² may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹³³ wherein R¹³³ represents H or (C₁-C₃)alkyl;                -   4.4.d3) —OR¹³⁴ wherein R¹³⁴ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; or                -   4.4.d4) NR¹³⁵R¹³⁶ wherein R¹³⁵ and R¹³⁶ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹³⁵ and R¹³⁶ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹³⁷ wherein R¹³⁷ represents H or (C₁-C₃)alkyl;                    and            -    j represents 1, 2, or 3;

        -   4.5)

wherein

-   -   -   -   X represents C or N;            -   R¹³⁸ represents            -   4.5.a) (C₁-C₄)alkyl, which may optionally bear up to 3                substituents independently selected from            -    4.5.a1) halogen;            -    4.5.a2) OR¹³⁹ wherein R¹³⁹ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or —(C₁-C₃)mono- or                di-alkylamino;            -    4.5.a3) —NR¹⁴⁰R¹⁴¹ in which R¹⁴⁰ and R¹⁴¹ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen or OR^(141a) wherein R^(141a) represents H                or (C₁-C₃)alkyl, or R¹⁴⁰ and R¹⁴¹ may be joined and                taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR¹⁴²                wherein R¹⁴² represents H or (C₁-C₃)alkyl; and            -    4.5.a4) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;            -   4.5.b) —(C₃-C₆)cycloalkyl which may optionally bear up                to 2 substituents independently selected from            -    4.5.b1) halogen; and            -    4.5.b2) OR¹⁴³ wherein R¹⁴³ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;            -   4.5.c) OR¹⁴⁴ wherein            -    R¹⁴⁴ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl;                or (C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -    4.5.c1) halogen;            -    4.5.c2) OR¹⁴⁵ wherein R¹⁴⁵ represents H or (C₁-C₃)alkyl                which may optionally bear (C₁-C₃)mono- or di-alkylamino;                and            -    4.5.c3) NR¹⁴⁶R¹⁴⁷ in which R¹⁴⁶ and R¹⁴⁷³ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁴⁶ and R¹⁴⁷ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁴⁸ wherein R¹⁴⁸                represents H or (C₁-C₃)alkyl;            -   4.5.d) —C(O)—OR¹⁴⁹ wherein R¹⁴⁹ represents H or                —(C₁-C₄)alkyl which may optionally bear up to 3                halogens;            -   4.5.e) —C(O)—NR¹⁵⁰R¹⁵¹ wherein            -    R¹⁵⁰ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R¹⁵¹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with                -   4.5.e1) halogen;                -   4.5.e2) a 5-6 membered heteroaromatic containing up                    to two heteroatoms selected from O, S, and N;                -   4.5.e3) phenyl;                -   4.5.e4) —SO₂CH₃;                -   4.5.e5) —OR¹⁵² wherein R¹⁵² represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; or                -   4.5.e6) —NR¹⁵³R¹⁵⁴ in which R¹⁵³ and R¹⁵⁴ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹⁵³ and R¹⁵⁴ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹⁵⁵ wherein R¹⁵⁵ represents H or (C₁-C₃)alkyl;            -   4.5.f) —N(R¹⁵⁶)—C(O)—R¹⁵⁷ wherein            -    R¹⁵⁶ represents H or (C₁-C₃)alkyl; and            -    R¹⁵⁷ represents H, optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -    4.5.f1) optionally substituted phenyl,            -    4.5.f2) OR¹⁵⁸ wherein R¹⁵⁸ represents H or                (C₁-C₃)alkyl, or            -    4.5.f3) NR¹⁵⁹R¹⁶⁰ wherein R¹⁵⁹ and R¹⁶⁰ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁵⁹ and R¹⁶⁰ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁶¹ wherein R¹⁶¹                represents H or (C₁-C₃)alkyl;            -   4.5.g) —SO₂NR¹⁶²R¹⁶³ wherein            -    R¹⁶² represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R¹⁶³ represents H or —(C₁-C₄)alkyl which is optionally                substituted with                -   4.5.g1) halogen;                -   4.5.g2) a 5-6 membered heteroaromatic containing up                    to two heteroatoms selected from O, S, and N;                -   4.5.g3) phenyl;                -   4.5.g4) —SO₂CH₃;                -   4.5.g5) —OR¹⁶⁴ wherein R¹⁶⁴ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; or                -   4.5.g6) —NR¹⁶⁵R¹⁶⁶ in which R¹⁶⁵ and R¹⁶⁶ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹⁶⁵ and R¹⁶⁶ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹⁶⁷ wherein R¹⁶⁷ represents H or (C₁-C₃)alkyl;            -   4.5.h) —N(R¹⁶⁸)—SO₂—R¹⁶⁹ wherein            -    R¹⁶⁸ represents H or (C₁-C₃)alkyl, and            -    R¹⁶⁹ represents H, optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -    4.5.h1) halogen,            -    4.5.h2) optionally substituted phenyl,            -    4.5.h3) OR¹⁷⁰ wherein R¹⁷⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen, or            -    4.5.h4) NR¹⁷¹R¹⁷² wherein R¹⁷¹ and R¹⁷² are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁷¹ and R¹⁷² may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁷³ wherein R¹⁷³                represents H or (C₁-C₃)alkyl;            -   4.5.i) —NR¹⁷⁴R¹⁷⁵ in which R¹⁷⁴ and R¹⁷⁵ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen or OR^(175a) wherein R^(175a) represents H                or (C₁-C₃)alkyl, or R¹⁷⁴ and R¹⁷⁵ may be joined and                taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR¹⁷⁶                wherein R¹⁷⁶ represents H or (C₁-C₃)alkyl;            -   4.5.j) halogen;            -   4.5.k) optionally substituted phenyl;            -   4.5.l) NO₂;            -   4.5.m) CN; or            -   4.5.n) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N; and

        -   k represents 0, 1, or 2;

        -   4.6)

wherein R¹⁷⁷ represents H or —(C₁-C₃)alkyl; and

-   -   -   -   m represents 1, 2, or 3:

        -   4.7)

wherein

-   -   -   -   n represents 1, 2, or 3; and            -   p represents 0, 1, or 2;

        -   4.8)

wherein

-   -   -   -   q represents 1, 2, or 3;

        -   4.9)

wherein

-   -   -   -   R¹⁷⁸ represents            -    4.9.a) H;            -    4.9.b) —(C₁-C₃)alkyl which may optionally bear halogen                or —OR¹⁷⁹ in which R¹⁷⁹ represents H or (C₁-C₃)alkyl                optionally substituted with halogen;            -    4.9.c) —SO₂R¹⁸⁰ wherein R¹⁸⁰ represents optionally                substituted phenyl or —(C₁-C₃)alkyl, which may be                substituted with halogen or —OR¹⁸¹ wherein R¹⁸¹                represents H or (C₁-C₃)alkyl which may optionally bear                halogen;            -    4.9.d) —C(O)R¹⁸² wherein R¹⁸² represents optionally                substituted phenyl or —(C₁-C₃)alkyl which may optionally                bear up to 3 substituents independently selected from                -   4.9.d1) halogen;                -   4.9.d2) optionally substituted phenyl;                -   4.9.d3) —S(O)₂CH₃;                -   4.9.d4) OR¹⁸³ wherein R¹⁸³ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; and                -   4.9.d5) —NR¹⁸⁴R¹⁸⁵ in which R¹⁸⁴ and R¹⁸⁵ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen or OR^(185a) wherein                    R^(185a) represents H or (C₁-C₃)alkyl, or R¹⁸⁴ and                    R¹⁸⁵ may be joined and taken together with the N                    atom to which they are attached form a 5-6 membered                    ring which may optionally contain a ring member                    selected from O, S, and NR¹⁸⁶ wherein R¹⁸⁶                    represents H or (C₁-C₃)alkyl;            -    4.9.e) —C(O)OR¹⁸⁷ wherein R¹⁸⁷ represents (C₁-C₃)alkyl;                or            -    4.9.f) —C(O)—NR¹⁸⁸R¹⁸⁹ wherein R¹⁸⁸ and R¹⁸⁹ each                independently represents H or —(C₁-C₃)alkyl which may                optionally bear halogen, or R¹⁸⁸ and R¹⁸⁹ may be joined                and taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR¹⁹⁰                wherein R¹⁹⁰ represents H or (C₁-C₃)alkyl;            -   r represents 0, 1, or 2; and            -   s represents 0 or 1;

        -   4.10)

wherein

-   -   -   -   R¹⁹¹ presents            -    4.10.a) H;            -    4.10.b) —(C₁-C₃)alkyl which may optionally bear halogen                or —OR¹⁹² in which R¹⁹² represents H or (C₁-C₃)alkyl;            -    4.10.c) —SO₂R¹⁹³ wherein R¹⁹³ represents phenyl or                —(C₁-C₃)alkyl, both of which may be substituted with                halogen or —(C₁-C₃)alkyl;            -    4.10.d) —C(O)R¹⁹⁴ wherein R¹⁹⁴ represents (C₁-C₃)alkyl                which may optionally bear up to 3 substituents                independently selected from                -   4.10.d1) halogen;                -   4.10.d2) phenyl;                -   4.10.d3) —S(O)₂CH₃;                -   4.10.d4) OR¹⁹⁵ wherein R¹⁹⁵ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; and                -   4.10.d5) —NR¹⁹⁶R¹⁹⁷ in which R¹⁹⁶ and R¹⁹⁷ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen or OR^(197a) wherein                    R^(197a) represents H or (C₁-C₃)alkyl, or R¹⁹⁶ and                    R¹⁹⁷ may be joined and taken together with the N                    atom to which they are attached form a 5-6 membered                    ring which may optionally contain a ring member                    selected from O, S, and NR¹⁹⁸ wherein R¹⁹⁸                    represents H or (C₁-C₃)alkyl;            -    4.10.e) —C(O)OR¹⁹⁹ wherein R¹⁹⁹ represents                (C₁-C₃)alkyl; or            -    4.10.f) —C(O)—NR²⁰⁰R²⁰¹ wherein R²⁰⁰ and R²⁰¹ each                independently represents H or —(C₁-C₃)alkyl which may                optionally bear halogen, or R²⁰⁰ and R²⁰¹ may be joined                and taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR²⁰²                wherein R²⁰² represents H or (C₁-C₃)alkyl; and            -   X represents O, S, S(O), S(O)₂, or NR²⁰³ wherein            -    R²⁰³ represents H or —(C₁-C₃)alkyl; and            -   t represents 0, 1, or 2;

        -   4.11) halogen; or

        -   4.12) CN;

    -   or a pharmaceutically acceptable salt thereof.

In embodiment two, the present invention provides a compound of formula(I)

wherein

-   -   R¹ represents        -   1.1) phenyl which may optionally bear up to 4 substituents            independently selected from the group consisting of            -   1.1.a) (C₁-C₄)alkyl, which may optionally bear up to 3                substituents independently selected from            -    1.1.a1) halogen;            -    1.1.a2) OR⁵ wherein R⁵ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or —(C₁-C₃)mono- or                di-alkylamino;            -    1.1.a3) —NR⁶R⁷ in which R⁶ and R⁷ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen or                OR^(7a) wherein R^(7a) represents H or (C₁-C₃)alkyl, or                R⁶ and R⁷ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁸ wherein R⁸ represents H or (C₁-C₃)alkyl;                and            -    1.1.a4) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;            -   1.1.b) —(C₃-C₆)cycloalkyl which may optionally bear up                to 2 substituents independently selected from            -    1.1.b1) halogen;            -   1.1.c) OR¹⁰ wherein            -    R¹⁰ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl; or                (C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -    1.1.c1) halogen;            -    1.1.c2) OR¹¹ wherein R¹¹ represents H or (C₁-C₃)alkyl                which may optionally bear (C₁-C₃)mono- or di-alkylamino;                and            -    1.1.c3) NR¹²R¹³ in which R¹² and R¹³ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R¹² and R¹³ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR¹⁴ wherein R¹⁴ represents H or (C₁-C₃)alkyl;            -   1.1.e) —C(O)—NR¹⁶R¹⁷ wherein            -    R¹⁶ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R¹⁷ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -    1.1.e1) halogen;            -    1.1.e3) phenyl;            -    1.1.e4) —SO₂CH₃;            -    1.1.e5) —OR¹⁸ wherein R¹⁸ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -    1.1.e6) —NR¹⁹R²⁰ in which R¹⁹ and R²⁰ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R¹⁹ and R²⁰ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR²¹ wherein R²¹ represents H or (C₁-C₃)alkyl;            -   1.1.f) —N(R²²)—C(O)—R²³ wherein            -    R²² represents H or (C₁-C₃)alkyl; and            -    R²³ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -    1.1.f1) optionally substituted phenyl,            -    1.1.f2) OR²⁴ wherein R²⁴ represents H or (C₁-C₃)alkyl,                or            -    1.1.f3) NR²⁵R²⁶ wherein R²⁵ and R²⁶ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen, or                R²⁵ and R²⁶ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR²⁷ wherein R²⁷ represents H or (C₁-C₃)alkyl;            -   1.1.g) —SO₂NR²⁸R²⁹ wherein            -    R²⁸ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R²⁹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with:            -    1.1.g1) halogen;            -    1.1.g3) phenyl;            -    1.1.g4) —SO₂CH₃;            -    1.1.g5) —OR³⁰ wherein R³⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -    1.1.g6) —NR³¹R³² in which R³¹ and R³² are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R³¹ and R³² may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR³³ wherein R³³ represents H or (C₁-C₃)alkyl;            -   1.1.h) —N(R³⁴)—SO₂—R³⁵ wherein            -    R³⁴ represents H or (C₁-C₃)alkyl, and            -    R³⁵ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -    1.1.h1) halogen;            -    1.1.h2) optionally substituted phenyl,            -    1.1.h3) OR³⁶ wherein R³⁶ represents H or (C₁-C₃)alkyl,                or            -    1.1.h4) NR³⁷R³⁸ wherein R³⁷ and R³⁸ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen, or                R³⁷ and R³⁸ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR³⁹ wherein R³⁹ represents H or (C₁-C₃)alkyl;            -   1.1.i) —NR⁴⁰R⁴¹ in which R⁴⁰ and R⁴¹ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen or                OR⁴² in which R⁴² represents H or (C₁-C₃)alkyl, or R⁴⁰                and R⁴¹ may be joined and taken together with the N atom                to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁴³ wherein R⁴³ represents H or (C₁-C₃)alkyl;            -   1.1.j) halogen;            -   1.1.l) NO₂;            -   1.1.m) CN; and            -   1.1.n) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;    -   or    -   R¹ represents        -   1.2) a 5-6 membered aromatic heterocycle containing up to 3            heteroatoms independently selected from the group consisting            of N, O, and S; said R¹ heterocycle optionally bearing up to            4 substituents independently selected from the group            consisting of            -   1.2.a) (C₁-C₄)alkyl, which may optionally bear up to 3                substituents independently selected from            -    1.2.a1) halogen;            -    1.2.a2) OR⁴⁵ wherein R⁴⁵ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or —(C₁-C₃)mono- or                di-alkylamino;            -    1.2.a3) —NR⁴⁶R⁴⁷ in which R⁴⁶ and R⁴⁷ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen or                OR^(47a) wherein R^(47a) represents H or (C₁-C₃)alkyl,                or R⁴⁶ and R⁴⁷ may be joined and taken together with the                N atom to which they are attached form a 5-6 membered                ring which may optionally contain a ring member selected                from O, S, and NR⁴⁸ wherein R⁴⁸ represents H or                (C₁-C₃)alkyl; and            -    1.2.a4) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;            -   1.2.b) —(C₃-C₆)cycloalkyl which may optionally bear up                to 2 substituents independently selected from            -    1.2.b1) halogen;            -   1.2.c) OR⁵⁰ wherein            -    R⁵⁰ represents H; phenyl; benzyl; —(C₃-C₆)cycloalkyl;                or —(C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -    1.2.c1) halogen;            -    1.2.c2) OR⁵¹ wherein R⁵¹ represents H or (C₁-C₃)alkyl                which may optionally bear —(C₁-C₃)mono- or                di-alkylamino; and            -    1.2.c3) —NR⁵²R⁵³ in which R⁵² and R⁵³ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁵² and R⁵³ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁵⁴ wherein R⁵⁴ represents H or (C₁-C₃)alkyl;            -   1.2.e) —C(O)—NR⁵⁶R⁵⁷ wherein            -    R⁵⁶ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R⁵⁷ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -    1.2.e1) halogen;            -    1.2.e3) phenyl;            -    1.2.e4) —SO₂CH₃;            -    1.2.e5) —OR⁵⁸ wherein R⁵⁸ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -    1.2.e6) —NR⁵⁹R⁶⁰ in which R⁵⁹ and R⁶⁰ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁵⁹ and R⁶⁰ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁶¹ wherein R⁶¹ represents H or (C₁-C₃)alkyl;            -   1.2.f) —N(R⁶²)—C(O)—R⁶³ wherein            -    R⁶² represents H or (C₁-C₃)alkyl; and            -    R⁶³ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -    1.2.f1) optionally substituted phenyl,            -    1.2.f2) OR⁶⁴ wherein R⁶⁴ represents H or (C₁-C₃)alkyl,                or            -    1.2.f3) NR⁶⁵R⁶⁶ wherein R⁶⁵ and R⁶⁶ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁶⁵ and R⁶⁶ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁶⁷ wherein R⁶⁷ represents H or (C₁-C₃)alkyl;            -   1.2.g) —SO₂NR⁶⁸R⁶⁹ wherein            -    R⁶⁸ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R⁶⁹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -    1.2.g1) halogen;            -    1.2.g3) phenyl;            -    1.2.g4) —SO₂CH₃;            -    1.2.g5) —OR⁷⁰ wherein R⁷⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -    1.2.g6 —NR⁷¹R⁷² in which R⁷¹ and R⁷² are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁷¹ and R⁷² may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁷³ wherein R⁷³ represents H or (C₁-C₃)alkyl;            -   1.2.h) —N(R⁷⁴)—SO₂—R⁷⁵ wherein            -    R⁷⁴ represents H or (C₁-C₃)alkyl, and            -    R⁷⁵ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -    1.2.h1) halogen;            -    1.2.h2) optionally substituted phenyl,            -    1.2.h3) OR⁷⁶ wherein R⁷⁶ represents H or (C₁-C₃)alkyl,                or            -    1.2.h4) NR⁷⁷R⁷⁸ wherein R⁷⁷ and R⁷⁸ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁷⁷ and R⁷⁸ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁷⁹ wherein R⁷⁹ represents H or (C₁-C₃)alkyl;            -   1.2.i) —NR⁸⁰R⁸¹ in which R⁸⁰ and R⁸¹ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen or                OR^(81a) wherein R^(81a) represents H or (C₁-C₃)alkyl,                or R⁸⁰ and R⁸¹ may be joined and taken together with the                N atom to which they are attached faun a 5-6 membered                ring which may optionally contain a ring member selected                from O, S, and NR⁸² wherein R⁸² represents H or                (C₁-C₃)alkyl;            -   1.2.j) halogen;            -   1.2.k) optionally substituted phenyl;            -   1.2.l) NO₂;            -   1.2.m) CN; and            -   1.2.n) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;    -   R² represents halogen; —(C₁-C₅)alkyl which may optionally bear        halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen;    -   R³ represents        -   3.1) —(C₁-C₅)alkyl which is optionally substituted with            -   3.1.a) -halogen;            -   3.1.b) phenyl optionally substituted with halogen,                —(C₁-C₃)alkyl, or —(C₁-C₃)alkoxy,            -   3.1.c) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N, optionally                substituted with halogen or —(C₁-C₃)alkyl,            -   3.1.d) —CN,            -   3.1.e) —OR⁸³ wherein R⁸³ represents H or —(C₁-C₃)alkyl                which may optionally bear up to 3 substituents                independently selected from            -    3.1.e1) halogen;            -    3.1.e2) optionally substituted phenyl;            -    3.1.e3) —S(O)₂CH₃;            -    3.1.e4) OR⁸⁴ wherein R⁸⁴ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or —(C₁-C₃)mono- or                di-alkylamino; and            -    3.1.e5) —NR⁸⁵R⁸⁶ in which R⁸⁵ and R⁸⁶ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁸⁵ and R⁸⁶ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁸⁷ wherein R⁸⁷ represents H or (C₁-C₃)alkyl;            -   3.1.f) —(C₃-C₅)cycloalkyl which may optionally bear                halogen; or            -   3.1.g) —NR⁸⁹R⁹⁰ wherein            -    R⁸⁹ represents H or —(C₁-C₃)alkyl which may optionally                bear halogen; and            -    R⁹⁰ represents H or —(C₁-C₄)alkyl which is optionally                substituted with                -   3.1.g1) halogen;                -   3.1.g2) a 5-6 membered heteroaromatic containing up                    to two heteroatoms selected from O, S, and N;                -   3.1.g3) phenyl;                -   3.1.g4) —SO₂CH₃;                -   3.1.g5) —OR⁹¹ wherein R⁹¹ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; or                -   3.1.g6) —NR⁹²R⁹³ in which R⁹² and R⁹³ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R⁹² and R⁹³ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR⁹⁴ wherein R⁹⁴ represents H or (C₁-C₃)alkyl;                    or                -   3.1.g7) R⁸⁹ and R⁹⁰ may be joined and taken together                    with the N to which they are attached form an                    aromatic or nonaromatic 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR⁹⁵ wherein R⁹⁵ represents H or (C₁-C₃)alkyl;        -   3.2)

wherein

-   -   -   -   R⁹⁶ represents            -   3.2.a) H,            -   3.2.b) —(C₃-C₅)cycloalkyl which may optionally bear                halogen; or            -   3.2.c) —(C₁-C₅)alkyl which may optionally bear up to 3                substituents independently selected from            -    3.2.c1) halogen;            -    3.2.c2) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;            -    3.2.c3) phenyl;            -    3.2.c5) —OR⁹⁷ wherein R⁹⁷ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or —(C₁-C₃)mono- or                di-alkylamino; and            -    3.2.c6) —NR⁹⁸R⁹⁹ in which R⁹⁸ and R⁹⁹ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen or                OR^(99a) wherein R^(99a) represents H or (C₁-C₃)alkyl,                or R⁹⁸ and R⁹⁹ may be joined and taken together with the                N atom to which they are attached form a 5-6 membered                ring which may optionally contain a ring member selected                from O, S, and NR¹⁰⁰ wherein R¹⁰⁰ represents H or                (C₁-C₃)alkyl;

        -   3.3)

wherein R¹⁰¹ represents H or —(C₁-C₅)alkyl which may optionally bear upto 3 substituents independently selected from

-   -   -   -   3.3.a) halogen; and            -   3.3.b) phenyl;

        -   3.4)

wherein

-   -   -   -   R¹⁰² represents H or —(C₁-C₃)alkyl which may optionally                bear halogen; and            -   R¹⁰³ represents H or —(C₁-C₅)alkyl which may optionally                bear up to 3 substituents independently selected from            -    3.4.a) halogen;            -    3.4.b) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;            -    3.4.c) phenyl;            -    3.4.d) —S(O)₂CH₃;            -    3.4.e) OR¹⁰⁴ wherein R¹⁰⁴ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; and            -    3.4.f) —NR¹⁰⁵R¹⁰⁶ in which R¹⁰⁵ and R¹⁰⁶ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁰⁵ and R¹⁰⁶ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁰⁷ wherein R¹⁰⁷                represents H or (C₁-C₃)alkyl;

        -   3.6) a 5-6 membered heteroaromatic containing up to two            heteroatoms selected from O, S, and N;

        -   3.7) halogen; or

        -   3.8) —CN;

    -   R⁴ represents        -   4.1) —(C₁-C₅)alkyl which is optionally substituted with            -   4.1.a) —(C₃-C₅)cycloalkyl which may optionally bear                halogen or OR¹⁰⁹ wherein R¹⁰⁹ represents H or                (C₁-C₃)alkyl;            -   4.1.b) -halogen;            -   4.1.c) —OR¹¹⁰ wherein R¹¹⁰ represents H or —(C₁-C₃)alkyl                which may optionally bear up to 3 substituents                independently selected from            -    4.1.c1) halogen;            -    4.1.c2) phenyl;            -    4.1.c4) OR¹¹¹ wherein R¹¹¹ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; and            -    4.1.c5) —NR¹¹²R¹¹³ in which R¹¹² and R¹¹³ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹¹² and R¹¹³ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹¹⁴ wherein R¹¹⁴                represents H or (C₁-C₃)alkyl;            -   4.1.d) —NR¹¹⁵R¹¹⁶ wherein            -    R¹¹⁵ represents H or —(C₁-C₃)alkyl which may optionally                bear halogen and            -    R¹¹⁶ represents H, optionally substituted phenyl, or                —(C₁-C₅)alkyl which may optionally bear up to 3                substituents independently selected from                -   4.1.d1) halogen;                -   4.1.d2) —S(O)₂CH₃;                -   4.1.d3) OR¹¹⁷ wherein R¹¹⁷ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; and                -   4.1.d4) NR¹¹⁸R¹¹⁹ in which R¹¹⁸ and R¹¹⁹ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹¹⁸ and R¹¹⁹ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹²⁰ wherein R¹²⁰ represents H or (C₁-C₃)alkyl;                    or            -   4.1.f) a 5-6 membered aromatic heterocycle containing up                to two heteroatoms selected from O, S, and N;        -   4.2)

wherein R¹²¹ represents —(C₁-C₃)alkyl which may optionally bear halogenor —OR¹²² in which R¹²² represents H or —(C₁-C₃)alkyl;

-   -   -   -   d represents 1, 2, or 3;            -   e represents 0 or 1;            -   f represents 0, 1, or 2;

        -   4.3)

wherein R¹²³ represents —(C₁-C₃)alkyl which may optionally bear halogenor —OR¹²⁴ in which R¹²⁴ represents H or —(C₁-C₃)alkyl;

-   -   -   -   g represents 1, 2, or 3;            -   h represents 0, 1, or 2;

        -   4.4)

wherein

-   -   -   -   R¹²⁵ represents            -    4.4.a) H;            -    4.4.b) —(C₁-C₃)alkyl which may optionally bear halogen                or —OR¹²⁶ in which R¹²⁶ represents H or —(C₁-C₃)alkyl                which in turn is optionally substituted with halogen;            -    4.4.c) —SO₂R¹²⁷ wherein R¹²⁷ represents optionally                substituted phenyl, or —(C₁-C₃)alkyl which may                optionally bear halogen or OR¹²⁸ wherein R¹²⁸ represents                H or (C₁-C₃)alkyl;            -    4.4.d) —C(O)R¹²⁹ wherein                -   R¹²⁹ represents                -   4.4.d1) optionally substituted phenyl,                -   4.4.d2) —(C₁-C₃)alkyl which may optionally bear up                    to 3 substituents independently selected from                -    4.4.d2.1) halogen;                -    4.4.d2.4) —OR¹³⁰ wherein R¹³⁰ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; and                -    4.4.d2.5) —NR¹³¹R¹³² in which R¹³¹ and R¹³² are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹³¹ and R¹³² may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹³³ wherein R¹³³ represents H or (C₁-C₃)alkyl;                -   4.4.d3) —OR¹³⁴ wherein R¹³⁴ represents (C₁-C₃)alkyl                    which may optionally bear halogen; or                -   4.4.d4) NR¹³⁵R¹³⁶ wherein R¹³⁵ and R¹³⁶ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹³⁵ and R¹³⁶ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹³⁷ wherein R¹³⁷ represents H or (C₁-C₃)alkyl;                    and            -    j represents 1, 2, or 3;

        -   4.5)

wherein

-   -   -   -   X represents C or N;            -   R¹³⁸ represents            -   4.5.a) (C₁-C₄)alkyl, which may optionally bear up to 3                substituents independently selected from            -    4.5.a1) halogen;            -    4.5.a2) OR¹³⁹ wherein R¹³⁹ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or —(C₁-C₃)mono- or                di-alkylamino;            -    4.5.a3) —NR¹⁴⁰R¹⁴¹ in which R¹⁴⁰ and R¹⁴¹ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen or OR^(141a) wherein R^(141a) represents H                or (C₁-C₃)alkyl, or R¹⁴⁰ and R¹⁴¹ may be joined and                taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR¹⁴²                wherein R¹⁴² represents H or (C₁-C₃)alkyl; and            -    4.5.a4) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;            -   4.5.b) —(C₃-C₆)cycloalkyl which may optionally bear up                to 2 substituents independently selected from            -    4.5.b1) halogen;            -   4.5.c) OR¹⁴⁴ wherein            -    R¹⁴⁴ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl;                or (C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -    4.5.c1) halogen;            -    4.5.c2) OR¹⁴⁵ wherein R¹⁴⁵ represents H or (C₁-C₃)alkyl                which may optionally bear (C₁-C₃)mono- or di-alkylamino;                and            -    4.5.c3) NR¹⁴⁶R¹⁴⁷ in which R¹⁴⁶ and R¹⁴⁷³ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁴⁶ and R¹⁴⁷ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁴⁸ wherein R¹⁴⁸                represents H or (C₁-C₃)alkyl;            -   4.5.e) —C(O)—NR¹⁵⁰R¹⁵¹ wherein            -    R¹⁵⁰ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R¹⁵¹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with                -   4.5.e1) halogen;                -   4.5.e3) phenyl;                -   4.5.e4) —SO₂CH₃;                -   4.5.e5) —OR¹⁵² wherein R¹⁵² represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; or                -   4.5.e6) —NR¹⁵³R¹⁵⁴ in which R¹⁵³ and R¹⁵⁴ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹⁵³ and R¹⁵⁴ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹⁵⁵ wherein R¹⁵⁵ represents H or (C₁-C₃)alkyl;            -   4.5.f) —N(R¹⁵⁶)—C(O)—R¹⁵⁷ wherein            -    R¹⁵⁶ represents H or (C₁-C₃)alkyl; and            -    R¹⁵⁷ represents H, optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -    4.5.f1) optionally substituted phenyl,            -    4.5.f2) OR¹⁵⁸ wherein R¹⁵⁸ represents H or                (C₁-C₃)alkyl, or            -    4.5.f3) NR¹⁵⁹R¹⁶⁰ wherein R¹⁵⁹ and R¹⁶⁰ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁵⁹ and R¹⁶⁰ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁶¹ wherein R¹⁶¹                represents H or (C₁-C₃)alkyl;            -   4.5.g) —SO₂NR¹⁶²R¹⁶³ wherein            -    R¹⁶² represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R¹⁶³ represents H or —(C₁-C₄)alkyl which is optionally                substituted with                -   4.5.g1) halogen;                -   4.5.g3) phenyl;                -   4.5.g4) —SO₂CH₃;                -   4.5.g5) —OR¹⁶⁴ wherein R¹⁶⁴ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; or                -   4.5.g6) —NR¹⁶⁵R¹⁶⁶ in which R¹⁶⁵ and R¹⁶⁶ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹⁶⁵ and R¹⁶⁶ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹⁶⁷ wherein R¹⁶⁷ represents H or (C₁-C₃)alkyl;            -   4.5.h) —N(R¹⁶⁸)—SO₂—R¹⁶⁹ wherein            -    R¹⁶⁸ represents H or (C₁-C₃)alkyl, and            -    R¹⁶⁹ represents H, optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -    4.5.h1) halogen,            -    4.5.h2) optionally substituted phenyl,            -    4.5.h3) OR¹⁷⁰ wherein R¹⁷⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen, or            -    4.5.h4) NR¹⁷¹R¹⁷² wherein R¹⁷¹ and R¹⁷² are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁷¹ and R¹⁷² may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁷³ wherein R¹⁷³                represents H or (C₁-C₃)alkyl;            -   4.5.i) —NR¹⁷⁴R¹⁷⁵ in which R¹⁷⁴ and R¹⁷⁵ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen or OR^(175a) wherein R^(175a) represents H                or (C₁-C₃)alkyl, or R¹⁷⁴ and R¹⁷⁵ may be joined and                taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR¹⁷⁶                wherein R¹⁷⁶ represents H or (C₁-C₃)alkyl;            -   4.5.j) halogen;            -   4.5.l) NO₂;            -   4.5.m) CN; or            -   4.5.n) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N; and

        -   k represents 0, 1, or 2;

        -   4.6)

wherein R¹⁷⁷ represents H or —(C₁-C₃)alkyl; and

-   -   -   -   m represents 1, 2, or 3;

        -   4.7)

wherein

-   -   -   -   n represents 1, 2, or 3; and            -   p represents 0, 1, or 2;

        -   4.8)

wherein

-   -   -   -   q represents 1, 2, or 3;

        -   4.9)

wherein

-   -   -   -   R¹⁷⁸ represents            -    4.9.a) H;            -    4.9.b) —(C₁-C₃)alkyl which may optionally bear halogen                or —OR¹⁷⁹ in which R¹⁷⁹ represents H or (C₁-C₃)alkyl                optionally substituted with halogen;            -    4.9.c) —SO₂R¹⁸⁰ wherein R¹⁸⁰ represents optionally                substituted phenyl or —(C₁-C₃)alkyl, which may be                substituted with halogen or —OR¹⁸¹ wherein R¹⁸¹                represents H or (C₁-C₃)alkyl which may optionally bear                halogen;            -    4.9.d) —C(O)R¹⁸² wherein R¹⁸² represents optionally                substituted phenyl or —(C₁-C₃)alkyl which may optionally                bear up to 3 substituents independently selected from                -   4.9.d1) halogen;                -   4.9.d2) optionally substituted phenyl;                -   4.9.d4) OR¹⁸³ wherein R¹⁸³ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; and                -   4.9.d5) —NR¹⁸⁴R¹⁸⁵ in which R¹⁸⁴ and R¹⁸⁵ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen or OR^(185a) wherein                    R^(185a) represents H or (C₁-C₃)alkyl, or R¹⁸⁴ and                    R¹⁸⁵ may be joined and taken together with the N                    atom to which they are attached form a 5-6 membered                    ring which may optionally contain a ring member                    selected from O, S, and NR¹⁸⁶ wherein R¹⁸⁶                    represents H or (C₁-C₃)alkyl;            -    4.9.e) —C(O)OR¹⁸⁷ wherein R¹⁸⁷ represents (C₁-C₃)alkyl;                or            -    4.9.f) —C(O)—NR¹⁸⁸R¹⁸⁹ wherein R¹⁸⁸ and R¹⁸⁹ each                independently represents H or —(C₁-C₃)alkyl which may                optionally bear halogen, or R¹⁸⁸ and R¹⁸⁹ may be joined                and taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR¹⁹⁰                wherein R¹⁹⁰ represents H or (C₁-C₃)alkyl;            -   r represents 0, 1, or 2; and            -   s represents 0 or 1;

        -   4.10)

wherein

-   -   -   -   R¹⁹¹ represents            -    4.10.a) H;            -    4.10.b) —(C₁-C₃)alkyl which may optionally bear halogen                or —OR¹⁹² in which R¹⁹² represents H or (C₁-C₃)alkyl;            -    4.10.c) —SO₂R¹⁹³ wherein R¹⁹³ represents phenyl or                —(C₁-C₃)alkyl, both of which may be substituted with                halogen or —(C₁-C₃)alkyl;            -    4.10.d) —C(O)R¹⁹⁴ wherein R¹⁹⁴ represents (C₁-C₃)alkyl                which may optionally bear up to 3 substituents                independently selected from                -   4.10.d1) halogen;                -   4.10.d2) phenyl;                -   4.10.d4) OR¹⁹⁵ wherein R¹⁹⁵ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; and                -   4.10.d5) —NR¹⁹⁶R¹⁹⁷ in which R¹⁹⁶ and R¹⁹⁷ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen or OR^(197a) wherein                    R^(197a) represents H or (C₁-C₃)alkyl, or R¹⁹⁶ and                    R¹⁹⁷ may be joined and taken together with the N                    atom to which they are attached form a 5-6 membered                    ring which may optionally contain a ring member                    selected from O, S, and NR¹⁹⁸ wherein R¹⁹⁸                    represents H or (C₁-C₃)alkyl;            -    4.10.e) —C(O)OR¹⁹⁹ wherein R¹⁹⁹ represents                (C₁-C₃)alkyl; or            -    4.10.f) —C(O)—NR²⁰⁰R²⁰¹ wherein R²⁰⁰ and R²⁰¹ each                independently represents H or —(C₁-C₃)alkyl which may                optionally bear halogen, or R²⁰⁰ and R²⁰¹ may be joined                and taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR²⁰²                wherein R²⁰² represents H or (C₁-C₃)alkyl; and            -   X represents O, S, S(O)₂, or NR²⁰³ wherein            -    R²⁰³ represents H or —(C₁-C₃)alkyl; and            -   t represents 0, 1, or 2;

        -   4.11) halogen; or

        -   4.12) —CN;

    -   or a pharmaceutically acceptable salt thereof.

In embodiment three, the present invention provides a compound offormula (I)

wherein

-   -   R¹ represents        -   1.1) phenyl which may optionally bear up to 4 substituents            independently selected from the group consisting of            -   1.1.a) (C₁-C₄)alkyl, which may optionally bear up to 3                substituents independently selected from            -    1.1.a1) halogen;            -    1.1.a2) OR⁵ wherein R⁵ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;            -    1.1.a3) —NR⁶R⁷ in which R⁶ and R⁷ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen or R⁶                and R⁷ may be joined and taken together with the N atom                to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁸ wherein R⁸ represents H or (C₁-C₃)alkyl;                and            -    1.1.a4) an imidazole, thiazole, oxazole, pyridine,                pyrazole, pyrimidine, isoxazole, isothiazole, thiophene,                or furan;            -   1.1.b) —(C₃-C₆)cycloalkyl which may optionally bear up                to 2 substituents independently selected from            -    1.1.b1) halogen;            -   1.1.c) OR¹⁰ wherein            -    R¹⁰ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl; or                (C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -    1.1.c1) halogen;            -    1.1.c2) OR¹¹ wherein R¹¹ represents H or (C₁-C₃)alkyl;                and            -    1.1.c3) NR¹²R¹³ in which R¹² and R¹³ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R¹² and R¹³ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR¹⁴ wherein R¹⁴ represents H or (C₁-C₃)alkyl;            -   1.1.e) —C(O)—NR¹⁶R¹⁷ wherein            -    R¹⁶ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R¹⁷ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -    1.1.e1) halogen;            -    1.1.e5) —OR¹⁸ wherein R¹⁸ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -    1.1.e6) —NR¹⁹R²⁰ in which R¹⁹ and R²⁰ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R¹⁹ and R²⁰ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR²¹ wherein R²¹ represents H or (C₁-C₃)alkyl;            -   1.1.f) —N(R²²)—C(O)—R²³ wherein            -    R²² represents H or (C₁-C₃)alkyl; and            -    R²³ represents optionally substituted phenyl, or                (C₁-C₄)alkyl;            -   1.1.g) —SO₂NR²⁸R²⁹ wherein            -    R²⁸ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R²⁹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with:            -    1.1.g1) halogen;            -    1.1.g4) —SO₂CH₃;            -    1.1.g5) —OR³⁰ wherein R³⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -    1.1.g6) —NR³¹R³² in which R³¹ and R³² are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R³¹ and R³² may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR³³ wherein R³³ represents H or (C₁-C₃)alkyl;            -   1.1.h) —N(R³⁴)—SO₂—R³⁵ wherein            -    R³⁴ represents H or (C₁-C₃)alkyl, and            -    R³⁵ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -    1.1.h1) halogen;            -   1.1.i) —NR⁴⁰R⁴¹ in which R⁴⁰ and R⁴¹ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen or                OR⁴² in which R⁴² represents H or (C₁-C₃)alkyl, or R⁴⁰                and R⁴¹ may be joined and taken together with the N atom                to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁴³ wherein R⁴³ represents H or (C₁-C₃)alkyl;            -   1.1.j) halogen;            -   1.1.l) NO₂;            -   1.1.m) CN; and            -   1.1.n) an imidazole, thiazole, oxazole, pyridine,                pyrazole, pyrimidine, isoxazole, isothiazole, thiophene,                or furan;    -   or    -   R¹ represents        -   1.2) a 5-6 membered aromatic heterocycle selected from            imidazole, thiazole, oxazole, pyridine, pyrazole,            pyrimidine, isoxazole, isothiazole, thiophene, and furan;            said R¹ heterocycle optionally bearing up to 4 substituents            independently selected from the group consisting of            -   1.2.a) (C₁-C₄)alkyl, which may optionally bear up to 3                substituents independently selected from            -    1.2.a1) halogen;            -    1.2.a2) OR⁴⁵ wherein R⁴⁵ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;            -    1.2.a3) —NR⁴⁶R⁴⁷ in which R⁴⁶ and R⁴⁷ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁴⁶ and R⁴⁷ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁴⁸ wherein R⁴⁸ represents H or (C₁-C₃)alkyl;                and            -    1.2.a4) an imidazole, thiazole, oxazole, pyridine,                pyrazole, pyrimidine, isoxazole, isothiazole, thiophene,                or furan;            -   1.2.b) —(C₃-C₆)cycloalkyl which may optionally bear up                to 2 substituents independently selected from            -    1.2.b1) halogen;            -   1.2.c) OR⁵⁰ wherein            -    R⁵⁰ represents H; phenyl; benzyl; —(C₃-C₆)cycloalkyl;                or —(C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -    1.2.c1) halogen;            -   1.2.e) —C(O)—NR⁵⁶R⁵⁷ wherein            -    R⁵⁶ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R⁵⁷ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -    1.2.e1) halogen; or            -    1.2.e5) —OR⁵⁸ wherein R⁵⁸ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;            -   1.2.f) —N(R⁶²)—C(O)—R⁶³ wherein            -    R⁶² represents H or (C₁-C₃)alkyl; and            -    R⁶³ represents optionally substituted phenyl, or                (C₁-C₄)alkyl;            -   1.2.g) —SO₂NR⁶⁸R⁶⁹ wherein            -    R⁶⁸ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R⁶⁹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -    1.2.g1) halogen; or            -    1.2.g5) —OR⁷⁰ wherein R⁷⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;            -   1.2.h) —N(R⁷⁴)—SO₂—R⁷⁵ wherein            -    R⁷⁴ represents H or (C₁-C₃)alkyl, and            -    R⁷⁵ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -    1.2.h1) halogen;            -   1.2.i) —NR⁸⁰R⁸¹ in which R⁸⁰ and R⁸¹ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen or                OR^(81a) wherein R^(81a) represents H or (C₁-C₃)alkyl,                or R⁸⁰ and R⁸¹ may be joined and taken together with the                N atom to which they are attached form a 5-6 membered                ring which may optionally contain a ring member selected                from O, S, and NR⁸² wherein R⁸² represents H or                (C₁-C₃)alkyl;            -   1.2.j) halogen;            -   1.2.k) optionally substituted phenyl;            -   1.2.l) NO₂;            -   1.2.m) CN; and            -   1.2.n) an imidazole, thiazole, oxazole, pyridine,                pyrazole, pyrimidine, isoxazole, isothiazole, thiophene,                or furan;    -   R² represents halogen; —(C₁-C₅)alkyl which may optionally bear        halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen;    -   R³ represents        -   3.1) —(C₁-C₅)alkyl which is optionally substituted with            -   3.1.a) -halogen;            -   3.1.b) phenyl optionally substituted with halogen,                —(C₁-C₃)alkyl, or —(C₁-C₃)alkoxy,            -   3.1.c) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N, optionally                substituted with halogen or —(C₁-C₃)alkyl,            -   3.1.d) —CN,            -   3.1.e) —OR⁸³ wherein R⁸³ represents H or —(C₁-C₃)alkyl                which may optionally bear up to 3 substituents                independently selected from            -    3.1.e1) halogen;            -    3.1.e2) optionally substituted phenyl;            -    3.1.e3) —S(O)₂CH₃;            -    3.1.e4) OR⁸⁴ wherein R⁸⁴ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or —(C₁-C₃)mono- or                di-alkylamino; and            -    3.1.e5) —NR⁸⁵R⁸⁶ in which R⁸⁵ and R⁸⁶ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁸⁵ and R⁸⁶ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁸⁷ wherein R⁸⁷ represents H or (C₁-C₃)alkyl;            -   3.1.f) —(C₃-C₅)cycloalkyl which may optionally bear                halogen; or            -   3.1.g) —NR⁸⁹R⁹⁰ wherein            -    R⁸⁹ represents H or —(C₁-C₃)alkyl which may optionally                bear halogen; and            -    R⁹⁰ represents H or —(C₁-C₄)alkyl which is optionally                substituted with                -   3.1.g1) halogen;                -   3.1.g2) a 5-6 membered heteroaromatic containing up                    to two heteroatoms selected from O, S, and N;                -   3.1.g3) phenyl;                -   3.1.g4) —SO₂CH₃;                -   3.1.g5) —OR⁹¹ wherein R⁹¹ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; or                -   3.1.g6) —NR⁹²R⁹³ in which R⁹² and R⁹³ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R⁹² and R⁹³ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR⁹⁴ wherein R⁹⁴ represents H or (C₁-C₃)alkyl;                    or                -   3.1.g7) R⁸⁹ and R⁹⁰ may be joined and taken together                    with the N to which they are attached form an                    aromatic or nonaromatic 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR⁹⁵ wherein R⁹⁵ represents H or (C₁-C₃)alkyl;        -   3.2)

wherein

-   -   -   -   R⁹⁶ represents            -   3.2.a) H,            -   3.2.b) —(C₃-C₅)cycloalkyl which may optionally bear                halogen; or            -   3.2.c) —(C₁-C₅)alkyl which may optionally bear up to 3                substituents independently selected from            -    3.2.c1) halogen;            -    3.2.c2) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;            -    3.2.c3) phenyl;            -    3.2.c5) —OR⁹⁷ wherein R⁹⁷ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or —(C₁-C₃)mono- or                di-alkylamino; and            -    3.2.c6) —NR⁹⁸R⁹⁹ in which R⁹⁸ and R⁹⁹ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen or                OR^(99a) wherein R^(99a) represents H or (C₁-C₃)alkyl,                or R⁹⁸ and R⁹⁹ may be joined and taken together with the                N atom to which they are attached form a 5-6 membered                ring which may optionally contain a ring member selected                from O, S, and NR¹⁰⁰ wherein R¹⁰⁰ represents H or                (C₁-C₃)alkyl;

        -   3.3)

wherein R¹⁰¹ represents H or —(C₁-C₅)alkyl which may optionally bear upto 3 substituents independently selected from

-   -   -   -   3.3.a) halogen; and            -   3.3.b) phenyl;

        -   3.4)

wherein

-   -   -   -   R¹⁰² represents H or —(C₁-C₃)alkyl which may optionally                bear halogen; and            -   R¹⁰³ represents H or —(C₁-C₅)alkyl which may optionally                bear up to 3 substituents independently selected from            -    3.4.a) halogen;            -    3.4.b) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;            -    3.4.c) phenyl;            -    3.4.d) —S(O)₂CH₃;            -    3.4.e) OR¹⁰⁴ wherein R¹⁰⁴ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; and            -    3.4.f) —NR¹⁰⁵R¹⁰⁶ in which R¹⁰⁵ and R¹⁰⁶ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁰⁵ and R¹⁰⁶ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁰⁷ wherein R¹⁰⁷                represents H or (C₁-C₃)alkyl;

        -   3.6) a 5-6 membered heteroaromatic containing up to two            heteroatoms selected from O, S, and N;

        -   3.7) halogen; or

        -   3.8) —CN;

    -   R⁴ represents        -   4.1) —(C₁-C₅)alkyl which is optionally substituted with            -   4.1.a) —(C₃-C₅)cycloalkyl which may optionally bear                halogen or OR¹⁰⁹ wherein R¹⁰⁹ represents H or                (C₁-C₃)alkyl;            -   4.1.b) -halogen;            -   4.1.c) —OR¹¹⁰ wherein R¹¹⁰ represents H or —(C₁-C₃)alkyl                which may optionally bear up to 3 substituents                independently selected from            -    4.1.c1) halogen;            -    4.1.c2) phenyl;            -    4.1.c4) OR¹¹¹ wherein R¹¹¹ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; and            -    4.1.c5) —NR¹¹²R¹¹³ in which R¹¹² and R¹¹³ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹¹² and R¹¹³ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹¹⁴ wherein R¹¹⁴                represents H or (C₁-C₃)alkyl;            -   4.1.d) —NR¹¹⁵R¹¹⁶ wherein            -    R¹¹⁵ represents H or —(C₁-C₃)alkyl which may optionally                bear halogen and            -    R¹¹⁶ represents H, optionally substituted phenyl, or                —(C₁-C₅)alkyl which may optionally bear up to 3                substituents independently selected from                -   4.1.d1) halogen;                -   4.1.d2) —S(O)₂CH₃;                -   4.1.d3) OR¹¹⁷ wherein R¹¹⁷ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; and                -   4.1.d4) —NR¹¹⁸R¹¹⁹ in which R¹¹⁸ and R¹¹⁹ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹¹⁸ and R¹¹⁹ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹²⁰ wherein R¹²⁰ represents H or (C₁-C₃)alkyl;                    or            -   4.1.f) a 5-6 membered aromatic heterocycle containing up                to two heteroatoms selected from O, S, and N;        -   4.2)

wherein R¹²¹ represents —(C₁-C₃)alkyl which may optionally bear halogenor —OR¹²² in which R¹²² represents H or —(C₁-C₃)alkyl;

-   -   -   -   d represents 1, 2, or 3;            -   e represents 0 or 1;            -   f represents 0, 1, or 2;

        -   4.3)

wherein R¹²³ represents —(C₁-C₃)alkyl which may optionally bear halogenor —OR¹²⁴ in which R¹²⁴ represents H or —(C₁-C₃)alkyl;

-   -   -   -   g represents 1, 2, or 3;            -   h represents 0, 1, or 2;

        -   4.4)

wherein

-   -   -   -   R¹²⁵ represents            -    4.4.a) H;            -    4.4.b) —(C₁-C₃)alkyl which may optionally bear halogen                or —OR¹²⁶ in which R¹²⁶ represents H or —(C₁-C₃)alkyl                which in turn is optionally substituted with halogen;            -    4.4.c) —SO₂R¹²⁷ wherein R¹²⁷ represents optionally                substituted phenyl, or —(C₁-C₃)alkyl which may                optionally bear halogen or OR¹²⁸ wherein R¹²⁸ represents                H or (C₁-C₃)alkyl;            -    4.4.d) —C(O)R¹²⁹ wherein                -   R¹²⁹ represents                -   4.4.d1) optionally substituted phenyl,                -   4.4.d2) —(C₁-C₃)alkyl which may optionally bear up                    to 3 substituents independently selected from                -    4.4.d2.1) halogen;                -    4.4.d2.4) —OR¹³⁰ wherein R¹³⁰ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; and                -    4.4.d2.5) —NR¹³¹R¹³² in which R¹³¹ and R¹³² are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹³¹ and R¹³² may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹³³ wherein R¹³³ represents H or (C₁-C₃)alkyl;                -   4.4.d3) —OR¹³⁴ wherein R¹³⁴ represents (C₁-C₃)alkyl                    which may optionally bear halogen; or                -   4.4.d4) NR¹³⁵R¹³⁶ wherein R¹³⁵ and R¹³⁶ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹³⁵ and R¹³⁶ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹³⁷ wherein R¹³⁷ represents H or (C₁-C₃)alkyl;                    and            -    j represents 1, 2, or 3;

        -   4.5)

wherein

-   -   -   -   X represents C or N;            -   R¹³⁸ represents            -   4.5.a) (C₁-C₄)alkyl, which may optionally bear up to 3                substituents independently selected from            -    4.5.a1) halogen;            -    4.5.a2) OR¹³⁹ wherein R¹³⁹ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or —(C₁-C₃)mono- or                di-alkylamino;            -    4.5.a3) —NR¹⁴⁰R¹⁴¹ in which R¹⁴⁰ and R¹⁴¹ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen or OR^(141a) wherein R^(141a) represents H                or (C₁-C₃)alkyl, or R¹⁴⁰ and R¹⁴¹ may be joined and                taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR¹⁴²                wherein R¹⁴² represents H or (C₁-C₃)alkyl; and            -    4.5.a4) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;            -   4.5.b) —(C₃-C₆)cycloalkyl which may optionally bear up                to 2 substituents independently selected from            -    4.5.b1) halogen;            -   4.5.c) OR¹⁴⁴ wherein            -    R¹⁴⁴ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl;                or (C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -    4.5.c1) halogen;            -    4.5.c2) OR¹⁴⁵ wherein R¹⁴⁵ represents H or (C₁-C₃)alkyl                which may optionally bear (C₁-C₃)mono- or di-alkylamino;                and            -    4.5.c3) NR¹⁴⁶R¹⁴⁷ in which R¹⁴⁶ and R¹⁴⁷³ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁴⁶ and R¹⁴⁷ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁴⁸ wherein R¹⁴⁸                represents H or (C₁-C₃)alkyl;            -   4.5.e) —C(O)—NR¹⁵⁰R¹⁵¹ wherein            -    R¹⁵⁰ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R¹⁵¹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with                -   4.5.e1) halogen;                -   4.5.e3) phenyl;                -   4.5.e4) —SO₂CH₃;                -   4.5.e5) —OR¹⁵² wherein R¹⁵² represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; or                -   4.5.e6) —NR¹⁵³R¹⁵⁴ in which R¹⁵³ and R¹⁵⁴ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹⁵³ and R¹⁵⁴ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹⁵⁵ wherein R¹⁵⁵ represents H or (C₁-C₃)alkyl;            -   4.5.f) —N(R¹⁵⁶)—C(O)—R¹⁵⁷ wherein            -    R¹⁵⁶ represents H or (C₁-C₃)alkyl; and            -    R¹⁵⁷ represents H, optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -    4.5.f1) optionally substituted phenyl,            -    4.5.f2) OR¹⁵⁸ wherein R¹⁵⁸ represents H or                (C₁-C₃)alkyl, or            -    4.5.f3) NR¹⁵⁹R¹⁶⁰ wherein R¹⁵⁹ and R¹⁶⁰ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁵⁹ and R¹⁶⁰ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁶¹ wherein R¹⁶¹                represents H or (C₁-C₃)alkyl;            -   4.5.g) —SO₂NR¹⁶²R¹⁶³ wherein            -    R¹⁶² represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R¹⁶³ represents H or —(C₁-C₄)alkyl which is optionally                substituted with                -   4.5.g1) halogen;                -   4.5.g3) phenyl;                -   4.5.g4) —SO₂CH₃;                -   4.5.g5) —OR¹⁶⁴ wherein R¹⁶⁴ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; or                -   4.5.g6) —NR¹⁶⁵R¹⁶⁶ in which R¹⁶⁵ and R¹⁶⁶ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹⁶⁵ and R¹⁶⁶ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹⁶⁷ wherein R¹⁶⁷ represents H or (C₁-C₃)alkyl;            -   4.5.h) —N(R¹⁶⁸)—SO₂—R¹⁶⁹ wherein            -    R¹⁶⁸ represents H or (C₁-C₃)alkyl, and            -    R¹⁶⁹ represents H, optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -    4.5.h1) halogen,            -    4.5.h2) optionally substituted phenyl,            -    4.5.h3) OR¹⁷⁰ wherein R¹⁷⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen, or            -    4.5.h4) NR¹⁷¹R¹⁷² wherein R¹⁷¹ and R¹⁷² are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁷¹ and R¹⁷² may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁷³ wherein R¹⁷³                represents H or (C₁-C₃)alkyl;            -   4.5.i) —NR¹⁷⁴R¹⁷⁵ in which R¹⁷⁴ and R¹⁷⁵ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen or OR^(175a) wherein R^(175a) represents H                or (C₁-C₃)alkyl, or R¹⁷⁴ and R¹⁷⁵ may be joined and                taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR¹⁷⁶                wherein R¹⁷⁶ represents H or (C₁-C₃)alkyl;            -   4.5.j) halogen;            -   4.5.l) NO₂;            -   4.5.m) CN; or            -   4.5.n) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N; and

        -   k represents 0, 1, or 2;

        -   4.6)

wherein R¹⁷⁷ represents H or —(C₁-C₃)alkyl; and

-   -   -   -   m represents 1, 2, or 3;

        -   4.7)

wherein

-   -   -   -   n represents 1, 2, or 3; and            -   p represents 0, 1, or 2;

        -   4.8)

wherein

-   -   -   -   q represents 1, 2, or 3;

        -   4.9)

wherein

-   -   -   -   R¹⁷⁸ represents            -    4.9.a) H;            -    4.9.b) —(C₁-C₃)alkyl which may optionally bear halogen                or —OR¹⁷⁹ in which R¹⁷⁹ represents H or (C₁-C₃)alkyl                optionally substituted with halogen;            -    4.9.c) —SO₂R¹⁸⁰ wherein R¹⁸⁰ represents optionally                substituted phenyl or —(C₁-C₃)alkyl, which may be                substituted with halogen or —OR¹⁸¹ wherein R¹⁸¹                represents H or (C₁-C₃)alkyl which may optionally bear                halogen;            -    4.9.d) —C(O)R¹⁸² wherein R¹⁸² represents optionally                substituted phenyl or —(C₁-C₃)alkyl which may optionally                bear up to 3 substituents independently selected from                -   4.9.d1) halogen;                -   4.9.d2) optionally substituted phenyl;                -   4.9.d4) OR¹⁸³ wherein R¹⁸³ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; and                -   4.9.d5) —NR¹⁸⁴R¹⁸⁵ in which R¹⁸⁴ and R¹⁸⁵ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen or OR^(185a) wherein                    R^(185a) represents H or (C₁-C₃)alkyl, or R¹⁸⁴ and                    R¹⁸⁵ may be joined and taken together with the N                    atom to which they are attached form a 5-6 membered                    ring which may optionally contain a ring member                    selected from O, S, and NR¹⁸⁶ wherein R¹⁸⁶                    represents H or (C₁-C₃)alkyl;            -    4.9.e) —C(O)OR¹⁸⁷ wherein R¹⁸⁷ represents (C₁-C₃)alkyl;                or            -    4.9.f) —C(O)—NR¹⁸⁸R¹⁸⁹ wherein R¹⁸⁸ and R¹⁸⁹ each                independently represents H or —(C₁-C₃)alkyl which may                optionally bear halogen, or R¹⁸⁸ and R¹⁸⁹ may be joined                and taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR¹⁹⁰                wherein R¹⁹⁰ represents H or (C₁-C₃)alkyl;            -   r represents 0, 1, or 2; and            -   s represents 0 or 1;

        -   4.10)

wherein

-   -   -   -   R¹⁹¹ represents            -    4.10.a) H;            -    4.10.b) —(C₁-C₃)alkyl which may optionally bear halogen                or —OR¹⁹² in which R¹⁹² represents H or (C₁-C₃)alkyl;            -    4.10.c) —SO₂R¹⁹³ wherein R¹⁹³ represents phenyl or                —(C₁-C₃)alkyl, both of which may be substituted with                halogen or —(C₁-C₃)alkyl;            -    4.10.d) —C(O)R¹⁹⁴ wherein R¹⁹⁴ represents (C₁-C₃)alkyl                which may optionally bear up to 3 substituents                independently selected from                -   4.10.d1) halogen;                -   4.10.d2) phenyl;                -   4.10.d4) OR¹⁹⁵ wherein R¹⁹⁵ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; and                -   4.10.d5) —NR¹⁹⁶R¹⁹⁷ in which R¹⁹⁶ and R¹⁹⁷ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen or OR^(197a) wherein                    R^(197a) represents H or (C₁-C₃)alkyl, or R¹⁹⁶ and                    R¹⁹⁷ may be joined and taken together with the N                    atom to which they are attached form a 5-6 membered                    ring which may optionally contain a ring member                    selected from O, S, and NR¹⁹⁸ wherein R¹⁹⁸                    represents H or (C₁-C₃)alkyl;            -    4.10.e) —C(O)OR¹⁹⁹ wherein R¹⁹⁹ represents                (C₁-C₃)alkyl; or            -    4.10.f) —C(O)—NR²⁰⁰R²⁰¹ wherein R²⁰⁰ and R²⁰¹ each                independently represents H or —(C₁-C₃)alkyl which may                optionally bear halogen, or R²⁰⁰ and R²⁰¹ may be joined                and taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR²⁰²                wherein R²⁰² represents H or (C₁-C₃)alkyl; and            -   X represents O, S, S(O)₂, or NR²⁰³ wherein            -    R²⁰³ represents H or —(C₁-C₃)alkyl; and            -   t represents 0, 1, or 2;

        -   4.11) halogen; or

        -   4.12) —CN;

    -   or a pharmaceutically acceptable salt thereof.

In embodiment four, the present invention provides a compound of formula(I)

wherein

-   -   R¹ represents        -   1.1) phenyl which may optionally bear up to 4 substituents            independently selected from the group consisting of            -   1.1.a) (C₁-C₄)alkyl, which may optionally bear up to 3                substituents independently selected from            -    1.1.a1) halogen;            -    1.1.a2) OR⁵ wherein R⁵ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;            -    1.1.a3) —NR⁶R⁷ in which R⁶ and R⁷ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen or R⁶                and R⁷ may be joined and taken together with the N atom                to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁸ wherein R⁸ represents H or (C₁-C₃)alkyl;                and            -    1.1.a4) an imidazole, thiazole, oxazole, pyridine,                pyrazole, pyrimidine, isoxazole, isothiazole, thiophene,                or furan;            -   1.1.b) —(C₃-C₆)cycloalkyl which may optionally bear up                to 2 substituents independently selected from            -    1.1.b1) halogen;            -   1.1.c) OR¹⁰ wherein            -    R¹⁰ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl; or                (C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -    1.1.c1) halogen;            -    1.1.c2) OR¹¹ wherein R¹¹ represents H or (C₁-C₃)alkyl;                and            -    1.1.c3) NR¹²R¹³ in which R¹² and R¹³ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R¹² and R¹³ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR¹⁴ wherein R¹⁴ represents H or (C₁-C₃)alkyl;            -   1.1.e) —C(O)—NR¹⁶R¹⁷ wherein            -    R¹⁶ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R¹⁷ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -    1.1.e1) halogen;            -    1.1.e5) —OR¹⁸ wherein R¹⁸ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -    1.1.e6) —NR¹⁹R²⁰ in which R¹⁹ and R²⁰ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R¹⁹ and R²⁰ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR²¹ wherein R²¹ represents H or (C₁-C₃)alkyl;            -   1.1.f) —N(R²²)—C(O)—R²³ wherein            -    R²² represents H or (C₁-C₃)alkyl; and            -    R²³ represents optionally substituted phenyl, or                (C₁-C₄)alkyl;            -   1.1.g) —SO₂NR²⁸R²⁹ wherein            -    R²⁸ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R²⁹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with:            -    1.1.g1) halogen;            -    1.1.g4) —SO₂CH₃;            -    1.1.g5) —OR³⁰ wherein R³⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -    1.1.g6) —NR³¹R³² in which R³¹ and R³² are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R³¹ and R³² may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR³³ wherein R³³ represents H or (C₁-C₃)alkyl;            -   1.1.h) —N(R³⁴)—SO₂—R³⁵ wherein            -    R³⁴ represents H or (C₁-C₃)alkyl, and            -    R³⁵ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -    1.1.h1) halogen;            -   1.1.i) —NR⁴⁰R⁴¹ in which R⁴⁰ and R⁴¹ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen or                OR⁴² in which R⁴² represents H or (C₁-C₃)alkyl, or R⁴⁰                and R⁴¹ may be joined and taken together with the N atom                to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁴³ wherein R⁴³ represents H or (C₁-C₃)alkyl;            -   1.1.j) halogen;            -   1.1.l) NO₂;            -   1.1.m) CN; and            -   1.1.n) an imidazole, thiazole, oxazole, pyridine,                pyrazole, pyrimidine, isoxazole, isothiazole, thiophene,                or furan;    -   or    -   R¹ represents        -   1.2) a 5-6 membered aromatic heterocycle selected from            imidazole, thiazole, oxazole, pyridine, pyrazole,            pyrimidine, isoxazole, isothiazole, thiophene, and furan;            said R¹ heterocycle optionally bearing up to 4 substituents            independently selected from the group consisting of            -   1.2.a) (C₁-C₄)alkyl, which may optionally bear up to 3                substituents independently selected from            -    1.2.a1) halogen;            -    1.2.a2) OR⁴⁵ wherein R⁴⁵ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;            -    1.2.a3) —NR⁴⁶R⁴⁷ in which R⁴⁶ and R⁴⁷ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁴⁶ and R⁴⁷ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁴⁸ wherein R⁴⁸ represents H or (C₁-C₃)alkyl;                and            -    1.2.a4) an imidazole, thiazole, oxazole, pyridine,                pyrazole, pyrimidine, isoxazole, isothiazole, thiophene,                or furan;            -   1.2.b) —(C₃-C₆)cycloalkyl which may optionally bear up                to 2 substituents independently selected from            -    1.2.b1) halogen;            -   1.2.c) OR⁵⁰ wherein            -    R⁵⁰ represents H; phenyl; benzyl; —(C₃-C₆)cycloalkyl;                or —(C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -    1.2.c1) halogen;            -   1.2.e) —C(O)—NR⁵⁶R⁵⁷ wherein            -    R⁵⁶ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R⁵⁷ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -    1.2.e1) halogen; or            -    1.2.e5) —OR⁵⁸ wherein R⁵⁸ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;            -   1.2.f) —N(R⁶²)—C(O)—R⁶³ wherein            -    R⁶² represents H or (C₁-C₃)alkyl; and            -    R⁶³ represents optionally substituted phenyl, or                (C₁-C₄)alkyl;            -   1.2.g) —SO₂NR⁶⁸R⁶⁹ wherein            -    R⁶⁸ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R⁶⁹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -    1.2.g1) halogen; or            -    1.2.g5) —OR⁷⁰ wherein R⁷⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;            -   1.2.h) —N(R⁷⁴)—SO₂—R⁷⁵ wherein            -    R⁷⁴ represents H or (C₁-C₃)alkyl, and            -    R⁷⁵ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -    1.2.h1) halogen;            -   1.2.i) —NR⁸⁰R⁸¹ in which R⁸⁰ and R⁸¹ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen or                OR^(81a) wherein R^(81a) represents H or (C₁-C₃)alkyl,                or R⁸⁰ and R⁸¹ may be joined and taken together with the                N atom to which they are attached form a 5-6 membered                ring which may optionally contain a ring member selected                from O, S, and NR⁸² wherein R⁸² represents H or                (C₁-C₃)alkyl;            -   1.2.j) halogen;            -   1.2.k) optionally substituted phenyl;            -   1.2.l) NO₂;            -   1.2.m) CN; and            -   1.2.n) an imidazole, thiazole, oxazole, pyridine,                pyrazole, pyrimidine, isoxazole, isothiazole, thiophene,                or furan;    -   R² represents halogen; —(C₁-C₅)alkyl which may optionally bear        halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen;    -   R³ represents        -   3.1) —(C₁-C₅)alkyl which is optionally substituted with            -   3.1.a) -halogen;            -   3.1.c) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N, optionally                substituted with halogen or —(C₁-C₃)alkyl;            -   3.1.d) —CN;            -   3.1.e) —OR⁸³ wherein R⁸³ represents H or —(C₁-C₃)alkyl                which may optionally bear up to 3 substituents                independently selected from            -    3.1.e1) halogen; or            -    3.1.e4) OR⁸⁴ wherein R⁸⁴ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;            -   3.1.f) —(C₃-C₅)cycloalkyl which may optionally bear                halogen; or            -   3.1.g) —NR⁸⁹R⁹⁰ wherein            -    R⁸⁹ represents H or —(C₁-C₃)alkyl which may optionally                bear halogen; and            -    R⁹⁰ represents H or —(C₁-C₄)alkyl which is optionally                substituted with                -   3.1.g1) halogen;                -   3.1.g4) —SO₂CH₃;                -   3.1.g5) —OR⁹¹ wherein R⁹¹ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; or                -   3.1.g7) R⁸⁹ and R⁹⁰ may be joined and taken together                    with the N to which they are attached form an                    aromatic or nonaromatic 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR⁹⁵ wherein R⁹⁵ represents H or (C₁-C₃)alkyl;        -   3.2)

wherein

-   -   -   -   R⁹⁶ represents            -   3.2.b) —(C₃-C₅)cycloalkyl which may optionally bear                halogen; or            -   3.2.c) —(C₁-C₅)alkyl which may optionally bear up to 3                substituents independently selected from            -    3.2.c1) halogen; and            -    3.2.c5) —OR⁹⁷ wherein R⁹⁷ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;

        -   3.3)

wherein R¹⁰¹ represents H or —(C₁-C₅)alkyl;

-   -   -   3.4)

wherein

-   -   -   -   R¹⁰² represents H or —(C₁-C₃)alkyl which may optionally                bear halogen; and            -   R¹⁰³ represents H or —(C₁-C₅)alkyl which may optionally                bear up to 3 substituents independently selected from            -    3.4.a) halogen;            -    3.4.d) —S(O)₂CH₃; and            -    3.4.e) OR¹⁰⁴ wherein R¹⁰⁴ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;

        -   3.7) halogen; or

        -   3.8) —CN;

    -   R⁴ represents        -   4.1) —(C₁-C₅)alkyl which is optionally substituted with            -   4.1.a) —(C₃-C₅)cycloalkyl which may optionally bear                halogen or OR¹⁰⁹ wherein R¹⁰⁹ represents H or                (C₁-C₃)alkyl;            -   4.1.b) -halogen;            -   4.1.c) —OR¹¹⁰ wherein R¹¹⁰ represents H or —(C₁-C₃)alkyl                which may optionally bear up to 3 substituents                independently selected from            -    4.1.c1) halogen;            -    4.1.c2) phenyl;            -    4.1.c4) OR¹¹¹ wherein R¹¹¹ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; and            -    4.1.c5) —NR¹¹²R¹¹³ in which R¹¹² and R¹¹³ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹¹² and R¹¹³ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹¹⁴ wherein R¹¹⁴                represents H or (C₁-C₃)alkyl;            -   4.1.d) —NR¹¹⁵R¹¹⁶ wherein            -    R¹¹⁵ represents H or —(C₁-C₃)alkyl which may optionally                bear halogen and            -    R¹¹⁶ represents H, optionally substituted phenyl, or                —(C₁-C₅)alkyl which may optionally bear up to 3                substituents independently selected from                -   4.1.d1) halogen;                -   4.1.d2) —S(O)₂CH₃;                -   4.1.d3) OR¹¹⁷ wherein R¹¹⁷ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; and                -   4.1.d4) —NR¹¹⁸R¹¹⁹ in which R¹¹⁸ and R¹¹⁹ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹¹⁸ and R¹¹⁹ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹²⁰ wherein R¹²⁰ represents H or (C₁-C₃)alkyl;                    or            -   4.1.f) a 5-6 membered aromatic heterocycle containing up                to two heteroatoms selected from O, S, and N;        -   4.2)

wherein R¹²¹ represents —(C₁-C₃)alkyl which may optionally bear halogenor —OR¹²² in which R¹²² represents H or —(C₁-C₃)alkyl;

-   -   -   -   d represents 1, 2, or 3;            -   e represents 0 or 1;            -   f represents 0, 1, or 2;

        -   4.3)

wherein R¹²³ represents —(C₁-C₃)alkyl which may optionally bear halogenor —OR¹²⁴ in which R¹²⁴ represents H or —(C₁-C₃)alkyl;

-   -   -   -   g represents 1, 2, or 3;            -   h represents 0, 1, or 2;

        -   4.4)

wherein

-   -   -   -   R¹²⁵ represents            -    4.4.a) H;            -    4.4.b) —(C₁-C₃)alkyl which may optionally bear halogen                or —OR¹²⁶ in which R¹²⁶ represents H or —(C₁-C₃)alkyl                which in turn is optionally substituted with halogen;            -    4.4.c) —SO₂R¹²⁷ wherein R¹²⁷ represents optionally                substituted phenyl, or —(C₁-C₃)alkyl which may                optionally bear halogen or OR¹²⁸ wherein R¹²⁸ represents                H or (C₁-C₃)alkyl;            -    4.4.d) —C(O)R¹²⁹ wherein                -   R¹²⁹ represents                -   4.4.d1) optionally substituted phenyl,                -   4.4.d2) —(C₁-C₃)alkyl which may optionally bear up                    to 3 substituents independently selected from                -    4.4.d2.1) halogen;                -    4.4.d2.4) —OR¹³⁰ wherein R¹³⁰ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; and                -    4.4.d2.5) —NR¹³¹R¹³² in which R¹³¹ and R¹³² are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹³¹ and R¹³² may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹³³ wherein R¹³³ represents H or (C₁-C₃)alkyl;                -   4.4.d3) —OR¹³⁴ wherein R¹³⁴ represents (C₁-C₃)alkyl                    which may optionally bear halogen; or                -   4.4.d4) NR¹³⁵R¹³⁶ wherein R¹³⁵ and R¹³⁶ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹³⁵ and R¹³⁶ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹³⁷ wherein R¹³⁷ represents H or (C₁-C₃)alkyl;                    and            -    j represents 1, 2, or 3;

        -   4.5)

wherein

-   -   -   -   X represents C or N;            -   R¹³⁸ represents            -   4.5.a) (C₁-C₄)alkyl, which may optionally bear up to 3                substituents independently selected from            -    4.5.a1) halogen;            -    4.5.a2) OR¹³⁹ wherein R¹³⁹ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or —(C₁-C₃)mono- or                di-alkylamino;            -    4.5.a3) —NR¹⁴⁰R¹⁴¹ in which R¹⁴⁰ and R¹⁴¹ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen or OR^(141a) wherein R^(141a) represents H                or (C₁-C₃)alkyl, or R¹⁴⁰ and R¹⁴¹ may be joined and                taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR¹⁴²                wherein R¹⁴² represents H or (C₁-C₃)alkyl; and            -    4.5.a4) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;            -   4.5.b) —(C₃-C₆)cycloalkyl which may optionally bear up                to 2 substituents independently selected from            -    4.5.b1) halogen;            -   4.5.c) OR¹⁴⁴ wherein            -    R¹⁴⁴ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl;                or (C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -    4.5.c1) halogen;            -    4.5.c2) OR¹⁴⁵ wherein R¹⁴⁵ represents H or (C₁-C₃)alkyl                which may optionally bear (C₁-C₃)mono- or di-alkylamino;                and            -    4.5.c3) NR¹⁴⁶R¹⁴⁷ in which R¹⁴⁶ and R¹⁴⁷³ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁴⁶ and R¹⁴⁷ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁴⁸ wherein R¹⁴⁸                represents H or (C₁-C₃)alkyl;            -   4.5.e) —C(O)—NR¹⁵⁰R¹⁵¹ wherein            -    R¹⁵⁰ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R¹⁵¹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with                -   4.5.e1) halogen;                -   4.5.e3) phenyl;                -   4.5.e4) —SO₂CH₃;                -   4.5.e5) —OR¹⁵² wherein R¹⁵² represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; or                -   4.5.e6) —NR¹⁵³R¹⁵⁴ in which R¹⁵³ and R¹⁵⁴ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹⁵³ and R¹⁵⁴ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹⁵⁵ wherein R¹⁵⁵ represents H or (C₁-C₃)alkyl;            -   4.5.f) —N(R¹⁵⁶)—C(O)—R¹⁵⁷ wherein            -    R¹⁵⁶ represents H or (C₁-C₃)alkyl; and            -    R¹⁵⁷ represents H, optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -    4.5.f1) optionally substituted phenyl,            -    4.5.f2) OR¹⁵⁸ wherein R¹⁵⁸ represents H or                (C₁-C₃)alkyl, or            -    4.5.f3) NR¹⁵⁹R¹⁶⁰ wherein R¹⁵⁹ and R¹⁶⁰ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁵⁹ and R¹⁶⁰ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁶¹ wherein R¹⁶¹                represents H or (C₁-C₃)alkyl;            -   4.5.g) —SO₂NR¹⁶²R¹⁶³ wherein            -    R¹⁶² represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and                -   R¹⁶³ represents H or —(C₁-C₄)alkyl which is                    optionally substituted with                -   4.5.g1) halogen;                -   4.5.g3) phenyl;                -   4.5.g4) —SO₂CH₃;                -   4.5.g5) —OR¹⁶⁴ wherein R¹⁶⁴ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; or                -   4.5.g6) —NR¹⁶⁵R¹⁶⁶ are in which R¹⁶⁵ and R¹⁶⁶ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹⁶⁵ and R¹⁶⁶ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹⁶⁷ wherein R¹⁶⁷ represents H or (C₁-C₃)alkyl;            -   4.5.h) —N(R¹⁶⁸)—SO₂—R¹⁶⁹ wherein            -    R¹⁶⁸ represents H or (C₁-C₃)alkyl, and            -    R¹⁶⁹ represents H, optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -    4.5.h1) halogen,            -    4.5.h2) optionally substituted phenyl,            -    4.5.h3) OR¹⁷⁰ wherein R¹⁷⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen, or            -    4.5.h4) NR¹⁷¹R¹⁷² wherein R¹⁷¹ and R¹⁷² are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁷¹ and R¹⁷² may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁷³ wherein R¹⁷³                represents H or (C₁-C₃)alkyl;            -   4.5.i) —NR¹⁷⁴R¹⁷⁵ in which R¹⁷⁴ and R¹⁷⁵ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen or OR^(175a) wherein R^(175a) represents H                or (C₁-C₃)alkyl, or R¹⁷⁴ and R¹⁷⁵ may be joined and                taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR¹⁷⁶                wherein R¹⁷⁶ represents H or (C₁-C₃)alkyl;            -   4.5.j) halogen;            -   4.5.l) NO₂;            -   4.5.m) CN; or            -   4.5.n) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N; and

        -   k represents 0, 1, or 2;

        -   4.6)

wherein R¹⁷⁷ represents H or —(C₁-C₃)alkyl; and

-   -   -   -   m represents 1, 2, or 3;

        -   4.7)

wherein

-   -   -   -   n represents 1, 2, or 3; and            -   p represents 0, 1, or 2;

        -   4.8)

wherein

-   -   -   -   q represents 1, 2, or 3;

        -   4.9)

wherein

-   -   -   -   R¹⁷⁸ represents            -    4.9.a) H;            -    4.9.b) —(C₁-C₃)alkyl which may optionally bear halogen                or —OR¹⁷⁹ in which R¹⁷⁹ represents H or (C₁-C₃)alkyl                optionally substituted with halogen;            -    4.9.c) —SO₂R¹⁸⁰ wherein R¹⁸⁰ represents optionally                substituted phenyl or —(C₁-C₃)alkyl, which may be                substituted with halogen or —OR¹⁸¹ wherein R¹⁸¹                represents H or (C₁-C₃)alkyl which may optionally bear                halogen;            -    4.9.d) —C(O)R¹⁸² wherein R¹⁸² represents optionally                substituted phenyl or —(C₁-C₃)alkyl which may optionally                bear up to 3 substituents independently selected from                -   4.9.d1) halogen;                -   4.9.d2) optionally substituted phenyl;                -   4.9.d4) OR¹⁸³ wherein R¹⁸³ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; and                -   4.9.d5) —NR¹⁸⁴R¹⁸⁵ in which R¹⁸⁴ and R¹⁸⁵ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen or OR^(185a) wherein                    R^(185a) represents H or (C₁-C₃)alkyl, or R¹⁸⁴ and                    R¹⁸⁵ may be joined and taken together with the N                    atom to which they are attached form a 5-6 membered                    ring which may optionally contain a ring member                    selected from O, S, and NR¹⁸⁶ wherein R¹⁸⁶                    represents H or (C₁-C₃)alkyl;            -    4.9.e) —C(O)OR¹⁸⁷ wherein R¹⁸⁷ represents (C₁-C₃)alkyl;                or            -    4.9.f) —C(O)—NR¹⁸⁸R¹⁸⁹ wherein R¹⁸⁸ and R¹⁸⁹ each                independently represents H or —(C₁-C₃)alkyl which may                optionally bear halogen, or R¹⁸⁸ and R¹⁸⁹ may be joined                and taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR¹⁹⁰                wherein R¹⁹⁰ represents H or (C₁-C₃)alkyl;            -   r represents 0, 1, or 2; and            -   s represents 0 or 1;

        -   4.10)

wherein

-   -   -   -   R¹⁹¹ represents            -    4.10.a) H;            -    4.10.b) —(C₁-C₃)alkyl which may optionally bear halogen                or —OR¹⁹² in which R¹⁹² represents H or (C₁-C₃)alkyl;            -    4.10.c) —SO₂R¹⁹³ wherein R¹⁹³ represents phenyl or                —(C₁-C₃)alkyl, both of which may be substituted with                halogen or —(C₁-C₃)alkyl;            -    4.10.d) —C(O)R¹⁹⁴ wherein R¹⁹⁴ represents (C₁-C₃)alkyl                which may optionally bear up to 3 substituents                independently selected from                -   4.10.d1) halogen;                -   4.10.d2) phenyl;                -   4.10.d4) OR¹⁹⁵ wherein R¹⁹⁵ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; and                -   4.10.d5) —NR¹⁹⁶R¹⁹⁷ in which R¹⁹⁶ and R¹⁹⁷ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen or OR^(197a) wherein                    R^(197a) represents H or (C₁-C₃)alkyl, or R¹⁹⁶ and                    R¹⁹⁷ may be joined and taken together with the N                    atom to which they are attached form a 5-6 membered                    ring which may optionally contain a ring member                    selected from O, S, and NR¹⁹⁸ wherein R¹⁹⁸                    represents H or (C₁-C₃)alkyl;            -    4.10.e) —C(O)OR¹⁹⁹ wherein R¹⁹⁹ represents                (C₁-C₃)alkyl; or            -    4.10.f) —C(O)—NR²⁰⁰R²⁰¹ wherein R²⁰⁰ and R²⁰¹ each                independently represents H or —(C₁-C₃)alkyl which may                optionally bear halogen, or R²⁰⁰ and R²⁰¹ may be joined                and taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR²⁰²                wherein R²⁰² represents H or (C₁-C₃)alkyl; and            -   X represents O, S, S(O)₂, or NR²⁰³ wherein            -    R²⁰³ represents H or —(C₁-C₃)alkyl; and            -   t represents 0, 1, or 2;

        -   4.11) halogen; or

        -   4.12) —CN;

    -   or a pharmaceutically acceptable salt thereof.

In embodiment five, the present invention provides a compound of formula(I)

wherein

-   -   R¹ represents        -   1.1) phenyl which may optionally bear up to 4 substituents            independently selected from the group consisting of            -   1.1.a) (C₁-C₄)alkyl, which may optionally bear up to 3                substituents independently selected from            -    1.1.a1) halogen;            -    1.1.a2) OR⁵ wherein R⁵ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;            -    1.1.a3) —NR⁶R⁷ in which R⁶ and R⁷ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen or R⁶                and R⁷ may be joined and taken together with the N atom                to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁸ wherein R⁸ represents H or (C₁-C₃)alkyl;                and            -    1.1.a4) an imidazole, thiazole, oxazole, pyridine,                pyrazole, pyrimidine, isoxazole, isothiazole, thiophene,                or furan;            -   1.1.b) —(C₃-C₆)cycloalkyl which may optionally bear up                to 2 substituents independently selected from            -    1.1.b1) halogen;            -   1.1.c) OR¹⁰ wherein            -    R¹⁰ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl; or                (C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -    1.1.c1) halogen;            -    1.1.c2) OR¹¹ wherein R¹¹ represents H or (C₁-C₃)alkyl;                and            -    1.1.c3) NR¹²R¹³ in which R¹² and R¹³ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R¹² and R¹³ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR¹⁴ wherein R¹⁴ represents H or (C₁-C₃)alkyl;            -   1.1.e) —C(O)—NR¹⁶R¹⁷ wherein            -    R¹⁶ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R¹⁷ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -    1.1.e1) halogen;            -    1.1.e5) —OR¹⁸ wherein R¹⁸ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -    1.1.e6) —NR¹⁹R²⁰ in which R¹⁹ and R²⁰ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R¹⁹ and R²⁰ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR²¹ wherein R²¹ represents H or (C₁-C₃)alkyl;            -   1.1.f) —N(R²²)—C(O)—R²³ wherein            -    R²² represents H or (C₁-C₃)alkyl; and            -    R²³ represents optionally substituted phenyl, or                (C₁-C₄)alkyl;            -   1.1.g) —SO₂NR²⁸R²⁹ wherein            -    R²⁸ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R²⁹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with:            -    1.1.g1) halogen;            -    1.1.g4) —SO₂CH₃;            -    1.1.g5) —OR³⁰ wherein R³⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -    1.1.g6) —NR³¹R³² in which R³¹ and R³² are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R³¹ and R³² may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR³³ wherein R³³ represents H or (C₁-C₃)alkyl;            -   1.1.h) —N(R³⁴)—SO₂—R³⁵ wherein            -    R³⁴ represents H or (C₁-C₃)alkyl, and            -    R³⁵ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -    1.1.h1) halogen;            -   1.1.i) —NR⁴⁰R⁴¹ in which R⁴⁰ and R⁴¹ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen or                OR⁴² in which R⁴² represents H or (C₁-C₃)alkyl, or R⁴⁰                and R⁴¹ may be joined and taken together with the N atom                to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁴³ wherein R⁴³ represents H or (C₁-C₃)alkyl;            -   1.1.j) halogen;            -   1.1.l) NO₂;            -   1.1.m) CN; and            -   1.1.n) an imidazole, thiazole, oxazole, pyridine,                pyrazole, pyrimidine, isoxazole, isothiazole, thiophene,                or furan;    -   or    -   R¹ represents        -   1.2) a 5-6 membered aromatic heterocycle selected from            imidazole, thiazole, oxazole, pyridine, pyrazole,            pyrimidine, isoxazole, isothiazole, thiophene, and furan;            said R¹ heterocycle optionally bearing up to 4 substituents            independently selected from the group consisting of            -   1.2.a) (C₁-C₄)alkyl, which may optionally bear up to 3                substituents independently selected from            -    1.2.a1) halogen;            -    1.2.a2) OR⁴⁵ wherein R⁴⁵ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;            -    1.2.a3) —NR⁴⁶R⁴⁷ in which R⁴⁶ and R⁴⁷ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁴⁶ and R⁴⁷ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁴⁸ wherein R⁴⁸ represents H or (C₁-C₃)alkyl;                and            -    1.2.a4) an imidazole, thiazole, oxazole, pyridine,                pyrazole, pyrimidine, isoxazole, isothiazole, thiophene,                or furan;            -   1.2.b) —(C₃-C₆)cycloalkyl which may optionally bear up                to 2 substituents independently selected from            -    1.2.b1) halogen;            -   1.2.c) OR⁵⁰ wherein            -    R⁵⁰ represents H; phenyl; benzyl; —(C₃-C₆)cycloalkyl;                or —(C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -    1.2.c1) halogen;            -   1.2.e) —C(O)—NR⁵⁶R⁵⁷ wherein            -    R⁵⁶ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R⁵⁷ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -    1.2.e1) halogen; or            -    1.2.e5) —OR⁵⁸ wherein R⁵⁸ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;            -   1.2.f) —N(R⁶²)—C(O)—R⁶³ wherein            -    R⁶² represents H or (C₁-C₃)alkyl; and            -    R⁶³ represents optionally substituted phenyl, or                (C₁-C₄)alkyl;            -   1.2.g) —SO₂NR⁶⁸R⁶⁹ wherein            -    R⁶⁸ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R⁶⁹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -    1.2.g1) halogen; or            -    1.2.g5) —OR⁷⁰ wherein R⁷⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -   1.2.h) —N(R⁷⁴)—SO₂—R⁷⁵ wherein            -    R⁷⁴ represents H or (C₁-C₃)alkyl, and            -    R⁷⁵ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -    1.2.h1) halogen;            -   1.2.i) —NR⁸⁰R⁸¹ in which R⁸⁰ and R⁸¹ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen or                OR^(81a) wherein R^(81a) represents H or (C₁-C₃)alkyl,                or R⁸⁰ and R⁸¹ may be joined and taken together with the                N atom to which they are attached form a 5-6 membered                ring which may optionally contain a ring member selected                from O, S, and NR⁸² wherein R⁸² represents H or                (C₁-C₃)alkyl;            -   1.2.j) halogen;            -   1.2.k) optionally substituted phenyl;            -   1.2.l) NO₂;            -   1.2.m) CN; and            -   1.2.n) an imidazole, thiazole, oxazole, pyridine,                pyrazole, pyrimidine, isoxazole, isothiazole, thiophene,                or furan;    -   R² represents halogen; —(C₁-C₅)alkyl which may optionally bear        halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen;    -   R³ represents        -   3.1) —(C₁-C₅)alkyl which is optionally substituted with            -   3.1.a) -halogen;            -   3.1.b) phenyl optionally substituted with halogen,                —(C₁-C₃)alkyl, or —(C₁-C₃)alkoxy,            -   3.1.c) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N, optionally                substituted with halogen or —(C₁-C₃)alkyl,            -   3.1.d) —CN,            -   3.1.e) —OR⁸³ wherein R⁸³ represents H or —(C₁-C₃)alkyl                which may optionally bear up to 3 substituents                independently selected from            -    3.1.e1) halogen;            -    3.1.e2) optionally substituted phenyl;            -    3.1.e3) —S(O)₂CH₃;            -    3.1.e4) OR⁸⁴ wherein R⁸⁴ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or —(C₁-C₃)mono- or                di-alkylamino; and            -    3.1.e5) —NR⁸⁵R⁸⁶ in which R⁸⁵ and R⁸⁶ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁸⁵ and R⁸⁶ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁸⁷ wherein R⁸⁷ represents H or (C₁-C₃)alkyl;            -   3.1.f) —(C₃-C₅)cycloalkyl which may optionally bear                halogen; or            -   3.1.g) —NR⁸⁹R⁹⁰ wherein            -    R⁸⁹ represents H or —(C₁-C₃)alkyl which may optionally                bear halogen; and            -    R⁹⁰ represents H or —(C₁-C₄)alkyl which is optionally                substituted with                -   3.1.g1) halogen;                -   3.1.g2) a 5-6 membered heteroaromatic containing up                    to two heteroatoms selected from O, S, and N;                -   3.1.g3) phenyl;                -   3.1.g4) —SO₂CH₃;                -   3.1.g5) —OR⁹¹ wherein R⁹¹ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; or                -   3.1.g6) —NR⁹²R⁹³ in which R⁹² and R⁹³ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R⁹² and R⁹³ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR⁹⁴ wherein R⁹⁴ represents H or (C₁-C₃)alkyl;                    or                -   3.1.g7) R⁸⁹ and R⁹⁰ may be joined and taken together                    with the N to which they are attached form an                    aromatic or nonaromatic 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR⁹⁵ wherein R⁹⁵ represents H or (C₁-C₃)alkyl;        -   3.2)

wherein

-   -   -   -   R⁹⁶ represents            -   3.2.a) H,            -   3.2.b) —(C₃-C₅)cycloalkyl which may optionally bear                halogen; or            -   3.2.c) —(C₁-C₅)alkyl which may optionally bear up to 3                substituents independently selected from            -    3.2.c1) halogen;            -    3.2.c2) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;            -    3.2.c3) phenyl;            -    3.2.c5) —OR⁹⁷ wherein R⁹⁷ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or —(C₁-C₃)mono- or                di-alkylamino; and            -    3.2.c6) —NR⁹⁸R⁹⁹ in which R⁹⁸ and R⁹⁹ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen or                OR^(99a) wherein R^(99a) represents H or (C₁-C₃)alkyl,                or R⁹⁸ and R⁹⁹ may be joined and taken together with the                N atom to which they are attached form a 5-6 membered                ring which may optionally contain a ring member selected                from O, S, and NR¹⁰⁰ wherein R¹⁰⁰ represents H or                (C₁-C₃)alkyl;

        -   3.3)

wherein R¹⁰¹ represents H or —(C₁-C₅)alkyl which may optionally bear upto 3 substituents independently selected from

-   -   -   -   3.3.a) halogen; and            -   3.3.b) phenyl;

        -   3.4)

wherein

-   -   -   -   R¹⁰² represents H or —(C₁-C₃)alkyl which may optionally                bear halogen; and            -   R¹⁰³ represents H or —(C₁-C₅)alkyl which may optionally                bear up to 3 substituents independently selected from            -    3.4.a) halogen;            -    3.4.b) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;            -    3.4.c) phenyl;            -    3.4.d) —S(O)₂CH₃;            -    3.4.e) OR¹⁰⁴ wherein R¹⁰⁴ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; and            -    3.4.f) —NR¹⁰⁵R¹⁰⁶ in which R¹⁰⁵ and R¹⁰⁶ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁰⁵ and R¹⁰⁶ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁰⁷ wherein R¹⁰⁷                represents H or (C₁-C₃)alkyl;

        -   3.6) a 5-6 membered heteroaromatic containing up to two            heteroatoms selected from O, S, and N;

        -   3.7) halogen; or

        -   3.8) —CN;

    -   R⁴ represents        -   4.1) —(C₁-C₅)alkyl which is optionally substituted with            -   4.1.b) -halogen;            -   4.1.c) —OR¹¹⁰ wherein R¹¹⁰ represents H or —(C₁-C₃)alkyl                which may optionally bear up to 3 substituents                independently selected from            -    4.1.c1) halogen; and            -    4.1.c5) —NR¹¹²R¹¹³ in which R¹¹² and R¹¹³ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹¹² and R¹¹³ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹¹⁴ wherein R¹¹⁴                represents H or (C₁-C₃)alkyl; or            -   4.1.d) —NR¹¹⁵R¹¹⁶ wherein            -    R¹¹⁵ represents H or —(C₁-C₃)alkyl which may optionally                bear halogen and            -    R¹¹⁶ represents H, optionally substituted phenyl, or                —(C₁-C₅)alkyl which may optionally bear up to 3                substituents independently selected from                -   4.1.d1) halogen;                -   4.1.d2) —S(O)₂CH₃;                -   4.1.d3) OR¹¹⁷ wherein R¹¹⁷ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; and                -   4.1.d4) —NR¹⁸R¹¹⁹ in which R¹¹⁸ and R¹¹⁹ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹¹⁸ and R¹¹⁹ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹²⁰ wherein R¹²⁰ represents H or (C₁-C₃)alkyl;        -   4.2)

wherein R¹²¹ represents —(C₁-C₃)alkyl which may optionally bear halogen;

-   -   -   -   d represents 1, 2, or 3;            -   e represents 0 or 1;            -   f represents 0, 1, or 2;

        -   4.3)

wherein R¹²³ represents —(C₁-C₃)alkyl which may optionally bear halogen;

-   -   -   -   g represents 1, 2, or 3;            -   h represents 0, 1, or 2;

        -   4.4)

wherein

-   -   -   -   R¹²⁵ represents            -    4.4.a) H;            -    4.4.b) —(C₁-C₃)alkyl which may optionally bear halogen;            -    4.4.c) —SO₂R¹²⁷ wherein R¹²⁷ represents optionally                substituted phenyl, or —(C₁-C₃)alkyl which may                optionally bear halogen;            -    4.4.d) —C(O)R¹²⁹ wherein                -   R¹²⁹ represents                -   4.4.d1) optionally substituted phenyl,                -   4.4.d2) —(C₁-C₃)alkyl which may optionally bear up                    to 3 substituents independently selected from                -    4.4.d2.1) halogen; and                -    4.4.d2.4) —OR¹³⁰ wherein R¹³⁰ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen;                -   4.4.d3) —OR¹³⁴ wherein R¹³⁴ represents (C₁-C₃)alkyl;                    or                -   4.4.d4) NR¹³⁵R¹³⁶ wherein R¹³⁵ and R¹³⁶ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen; and            -    j represents 1, 2, or 3;

        -   4.5)

wherein

-   -   -   -   X represents C or N;            -   R¹³⁸ represents            -   4.5.a) (C₁-C₄)alkyl, which may optionally bear up to 3                substituents independently selected from            -    4.5.a1) halogen;            -    4.5.a2) OR¹³⁹ wherein R¹³⁹ represents H or                (C_(r)—C₃)alkyl which may optionally bear halogen; and            -    4.5.a3) —NR¹⁴⁰R¹⁴¹ in which R¹⁴⁰ and R¹⁴¹ are                independently H or —(C₁-C₃)alkyl, or R¹⁴⁰ and R¹⁴¹ may                be joined and taken together with the N atom to which                they are attached form a 5-6 membered ring which may                optionally contain a ring member selected from O, S, and                NR¹⁴² wherein R¹⁴² represents H or (C₁-C₃)alkyl;            -   4.5.b) —(C₃-C₆)cycloalkyl which may optionally bear up                to 2 substituents independently selected from            -    4.5.b1) halogen;            -   4.5.c) OR¹⁴⁴ wherein            -    R¹⁴⁴ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl;                or (C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -    4.5.c1) halogen;            -    4.5.c2) OR¹⁴⁵ wherein R¹⁴⁵ represents H or                (C₁-C₃)alkyl; and            -    4.5.c3) NR¹⁴⁶R¹⁴⁷ in which R¹⁴⁶ and R¹⁴⁷³ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁴⁶ and R¹⁴⁷ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁴⁸ wherein R¹⁴⁸                represents H or (C₁-C₃)alkyl;            -   4.5.e) —C(O)—NR¹⁵⁰R¹⁵¹ wherein            -    R¹⁵⁰ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R¹⁵¹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with                -   4.5.e1) halogen; or                -   4.5.e6) —NR¹⁵³R¹⁵⁴ in which R¹⁵³ and R¹⁵⁴ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹⁵³ and R¹⁵⁴ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹⁵⁵ wherein R¹⁵⁵ represents H or (C₁-C₃)alkyl;            -   4.5.f) —N(R¹⁵⁶)—C(O)—R¹⁵⁷ wherein            -    R¹⁵⁶ represents H or (C₁-C₃)alkyl; and            -    R¹⁵⁷ represents H, optionally substituted phenyl, or                (C₁-C₄)alkyl;            -   4.5.g) —SO₂NR¹⁶²R¹⁶³ wherein            -    R¹⁶² represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R¹⁶³ represents H or —(C₁-C₄)alkyl which is optionally                substituted with                -   4.5.g1) halogen; or                -   4.5.g6) —NR¹⁶⁵R¹⁶⁶ in which R¹⁶⁵ and R¹⁶⁶ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹⁶⁵ and R¹⁶⁶ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹⁶⁷ wherein R¹⁶⁷ represents H or (C₁-C₃)alkyl;            -   4.5.h) —N(R¹⁶⁸)—SO₂—R¹⁶⁹ wherein            -    R¹⁶⁸ represents H or (C₁-C₃)alkyl, and            -    R¹⁶⁹ represents H, optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -    4.5.h1) halogen; or            -    4.5.h4) NR¹⁷¹R¹⁷² wherein R¹⁷¹ and R¹⁷² are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁷¹ and R¹⁷² may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁷³ wherein R¹⁷³                represents H or (C₁-C₃)alkyl;            -   4.5.i) —NR¹⁷⁴R¹⁷⁵ in which R¹⁷⁴ and R¹⁷⁵ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen or OR^(175a) wherein R^(175a) represents H                or (C₁-C₃)alkyl, or R¹⁷⁴ and R¹⁷⁵ may be joined and                taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR¹⁷⁶                wherein R¹⁷⁶ represents H or (C₁-C₃)alkyl;            -   4.5.j) halogen;            -   4.5.l) NO₂;            -   4.5.m) CN; or            -   4.5.n) an imidazole, thiazole, oxazole, pyridine,                pyrazole, pyrimidine, isoxazole, isothiazole, thiophene,                or furan; and

        -   k represents 0, 1, or 2;

        -   4.6)

wherein R¹⁷⁷ represents H or —(C₁-C₃)alkyl; and

-   -   -   -   m represents 1, 2, or 3;

        -   4.7)

wherein

-   -   -   -   n represents 1, 2, or 3; and            -   p represents 0, 1, or 2;

        -   4.8)

wherein

-   -   -   -   q represents 1, 2, or 3;

        -   4.9)

wherein

-   -   -   -   R¹⁷⁸ represents            -    4.9.a) H;            -    4.9.b) —(C₁-C₃)alkyl which may optionally bear halogen;            -    4.9.c) —SO₂R¹⁸⁰ wherein R¹⁸⁰ represents optionally                substituted phenyl or —(C₁-C₃)alkyl, which may be                substituted with halogen;            -    4.9.d) —C(O)R¹⁸² wherein R¹⁸² represents optionally                substituted phenyl or —(C₁-C₃)alkyl which may optionally                bear up to 3 substituents independently selected from                -   4.9.d1) halogen; and                -   4.9.d4) OR¹⁸³ wherein R¹⁸³ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen;            -    4.9.e) —C(O)OR¹⁸⁷ wherein R¹⁸⁷ represents (C₁-C₃)alkyl;                or            -    4.9.f) —C(O)—NR¹⁸⁸R¹⁸⁹ wherein R¹⁸⁸ and R¹⁸⁹ each                independently represents H or —(C₁-C₃)alkyl which may                optionally bear halogen;            -   r represents 0, 1, or 2; and            -   s represents 0 or 1;

        -   4.10)

wherein

-   -   -   -   R¹⁹¹ represents            -    4.10.a) H;            -    4.10.b) —(C₁-C₃)alkyl which may optionally bear                halogen;            -    4.10.c) —SO₂R¹⁹³ wherein R¹⁹³ represents phenyl or                —(C₁-C₃)alkyl, both of which may be substituted with                halogen;            -    4.10.d) —C(O)R¹⁹⁴ wherein R¹⁹⁴ represents (C₁-C₃)alkyl                which may optionally bear up to 3 substituents                independently selected from                -   4.10.d1) halogen;                -   4.10.d2) phenyl; and                -   4.10.d4) OR¹⁹⁵ wherein R¹⁹⁵ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen;            -    4.10.e) —C(O)OR¹⁹⁹ wherein R¹⁹⁹ represents                (C₁-C₃)alkyl; or            -    4.10.f) —C(O)—NR²⁰⁰R²⁰¹ wherein R²⁰⁰ and R²⁰¹ each                independently represents H or —(C₁-C₃)alkyl which may                optionally bear halogen;            -   X represents O, S, S(O)₂, or NR²⁰³ wherein            -    R²⁰³ represents H or —(C₁-C₃)alkyl; and            -   t represents 0, 1, or 2;

        -   4.11) halogen; or

        -   4.12) —CN;

    -   or a pharmaceutically acceptable salt thereof.

In embodiment six, the present invention provides a compound of formula(I)

wherein

-   -   R¹ represents        -   1.1) phenyl which may optionally bear up to 4 substituents            independently selected from the group consisting of            -   1.1.a) (C₁-C₄)alkyl, which may optionally bear up to 3                substituents independently selected from            -    1.1.a1) halogen;            -    1.1.a2) OR⁵ wherein R⁵ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;            -    1.1.a3) —NR⁶R⁷ in which R⁶ and R⁷ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen or R⁶                and R⁷ may be joined and taken together with the N atom                to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁸ wherein R⁸ represents H or (C₁-C₃)alkyl;                and            -    1.1.a4) an imidazole, thiazole, oxazole, pyridine,                pyrazole, pyrimidine, isoxazole, isothiazole, thiophene,                or furan;            -   1.1.b) —(C₃-C₆)cycloalkyl which may optionally bear up                to 2 substituents independently selected from            -    1.1.b1) halogen;            -   1.1.c) OR¹⁰ wherein            -    R¹⁰ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl; or                (C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -    1.1.c1) halogen;            -    1.1.c2) OR¹¹ wherein R¹¹ represents H or (C₁-C₃)alkyl;                and            -    1.1.c3) NR¹²R¹³ in which R¹² and R¹³ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R¹² and R¹³ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR¹⁴ wherein R¹⁴ represents H or (C₁-C₃)alkyl;            -   1.1.e) —C(O)—NR¹⁶R¹⁷ wherein            -    R¹⁶ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R¹⁷ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -    1.1.e1) halogen;            -    1.1.e5) —OR¹⁸ wherein R¹⁸ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -    1.1.e6) —NR¹⁹R²⁰ in which R¹⁹ and R²⁰ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R¹⁹ and R²⁰ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR²¹ wherein R²¹ represents H or (C₁-C₃)alkyl;            -   1.1.f) —N(R²²)—C(O)—R²³ wherein            -    R²² represents H or (C₁-C₃)alkyl; and            -    R²³ represents optionally substituted phenyl, or                (C₁-C₄)alkyl;            -   1.1.g) —SO₂NR²⁸R²⁹ wherein            -    R²⁸ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R²⁹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with:            -    1.1.g1) halogen;            -    1.1.g4) —SO₂CH₃;            -    1.1.g5) —OR³⁰ wherein R³⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -    1.1.g6) —NR³¹R³² in which R³¹ and R³² are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R³¹ and R³² may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR³³ wherein R³³ represents H or (C₁-C₃)alkyl;            -   1.1.h) —N(R³⁴)—SO₂—R³⁵ wherein            -    R³⁴ represents H or (C₁-C₃)alkyl, and            -    R³⁵ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -    1.1.h1) halogen;            -   1.1.i) —NR⁴⁰R⁴¹ in which R⁴⁰ and R⁴¹ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen or                OR⁴² in which R⁴² represents H or (C₁-C₃)alkyl, or R⁴⁰                and R⁴¹ may be joined and taken together with the N atom                to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁴³ wherein R⁴³ represents H or (C₁-C₃)alkyl;            -   1.1.j) halogen;            -   1.1.l) NO₂;            -   1.1.m) CN; and            -   1.1.n) an imidazole, thiazole, oxazole, pyridine,                pyrazole, pyrimidine, isoxazole, isothiazole, thiophene,                or furan;    -   or    -   R¹ represents        -   1.2) a 5-6 membered aromatic heterocycle selected from            imidazole, thiazole, oxazole, pyridine, pyrazole,            pyrimidine, isoxazole, isothiazole, thiophene, and furan;            said R¹ heterocycle optionally bearing up to 4 substituents            independently selected from the group consisting of            -   1.2.a) (C₁-C₄)alkyl, which may optionally bear up to 3                substituents independently selected from            -    1.2.a1) halogen;            -    1.2.a2) OR⁴⁵ wherein R⁴⁵ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;            -    1.2.a3) —NR⁴⁶R⁴⁷ in which R⁴⁶ and R⁴⁷ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁴⁶ and R⁴⁷ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁴⁸ wherein R⁴⁸ represents H or (C₁-C₃)alkyl;                and            -    1.2.a4) an imidazole, thiazole, oxazole, pyridine,                pyrazole, pyrimidine, isoxazole, isothiazole, thiophene,                or furan;            -   1.2.b) —(C₃-C₆)cycloalkyl which may optionally bear up                to 2 substituents independently selected from            -    1.2.b1) halogen;            -   1.2.c) OR⁵⁰ wherein            -    R⁵⁰ represents H; phenyl; benzyl; —(C₃-C₆)cycloalkyl;                or —(C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -    1.2.c1) halogen;            -   1.2.e) —C(O)—NR⁵⁶R⁵⁷ wherein            -    R⁵⁶ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R⁵⁷ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -    1.2.e1) halogen; or            -    1.2.e5) —OR⁵⁸ wherein R⁵⁸ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;            -   1.2.f) —N(R⁶²)—C(O)—R⁶³ wherein            -    R⁶² represents H or (C₁-C₃)alkyl; and            -    R⁶³ represents optionally substituted phenyl, or                (C₁-C₄)alkyl;            -   1.2.g) —SO₂NR⁶⁸R⁶⁹ wherein            -    R⁶⁸ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R⁶⁹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -    1.2.g1) halogen; or            -    1.2.g5) —OR⁷⁰ wherein R⁷⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;            -   1.2.h) —N(R⁷⁴)—SO₂—R⁷⁵ wherein            -    R⁷⁴ represents H or (C₁-C₃)alkyl, and            -    R⁷⁵ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -    1.2.h1) halogen;            -   1.2.i) —NR⁸⁰R⁸¹ in which R⁸⁰ and R⁸¹ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen or                OR^(81a) wherein R^(81a) represents H or (C₁-C₃)alkyl,                or R⁸⁰ and R⁸¹ may be joined and taken together with the                N atom to which they are attached form a 5-6 membered                ring which may optionally contain a ring member selected                from O, S, and NR⁸² wherein R⁸² represents H or                (C₁-C₃)alkyl;            -   1.2.j) halogen;            -   1.2.k) optionally substituted phenyl;            -   1.2.l) NO₂;            -   1.2.m) CN; and            -   1.2.n) an imidazole, thiazole, oxazole, pyridine,                pyrazole, pyrimidine, isoxazole, isothiazole, thiophene,                or furan;    -   R² represents halogen; —(C₁-C₅)alkyl which may optionally bear        halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen;    -   R³ represents        -   3.1) —(C₁-C₅)alkyl which is optionally substituted with            -   3.1.a) -halogen;            -   3.1.c) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N, optionally                substituted with halogen or —(C₁-C₃)alkyl,            -   3.1.d) —CN,            -   3.1.e) —OR⁸³ wherein R⁸³ represents H or —(C₁-C₃)alkyl                which may optionally bear up to 3 substituents                independently selected from            -    3.1.e1) halogen; and            -    3.1.e4) OR⁸⁴ wherein R⁸⁴ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;            -   3.1.f) —(C₃-C₅)cycloalkyl which may optionally bear                halogen; or            -   3.1.g) —NR⁸⁹R⁹⁰ wherein            -    R⁸⁹ represents H or —(C₁-C₃)alkyl which may optionally                bear halogen; and            -    R⁹⁰ represents H or —(C₁-C₄)alkyl which is optionally                substituted with                -   3.1.g1) halogen;                -   3.1.g4) —SO₂CH₃;                -   3.1.g5) —OR⁹¹ wherein R⁹¹ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; or                -   3.1.g7) R⁸⁹ and R⁹⁰ may be joined and taken together                    with the N to which they are attached form an                    aromatic or nonaromatic 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR⁹⁵ wherein R⁹⁵ represents H or (C₁-C₃)alkyl;        -   3.2)

wherein

-   -   -   -   R⁹⁶ represents            -   3.2.b) —(C₃-C₅)cycloalkyl which may optionally bear                halogen; or            -   3.2.c) —(C₁-C₅)alkyl which may optionally bear up to 3                substituents independently selected from            -    3.2.c1) halogen; and            -    3.2.c5) —OR⁹⁷ wherein R⁹⁷ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;

        -   3.3)

wherein R¹⁰¹ represents H or —(C₁-C₅)alkyl;

-   -   -   3.4)

wherein

-   -   -   -   R¹⁰² represents H or —(C₁-C₃)alkyl which may optionally                bear halogen; and            -   R¹⁰³ represents H or —(C₁-C₅)alkyl which may optionally                bear up to 3 substituents independently selected from            -    3.4.a) halogen;            -    3.4.d) —S(O)₂CH₃; and            -    3.4.e) OR¹⁰⁴ wherein R¹⁰⁴ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;

        -   3.6) a 5-6 membered aromatic heterocycle selected from            imidazole, thiazole, oxazole, pyridine, pyrazole,            pyrimidine, isoxazole, isothiazole, thiophene, and furan;

        -   3.7) halogen; or

        -   3.8) —CN;

    -   R⁴ represents        -   4.1) —(C₁-C₅)alkyl which is optionally substituted with            -   4.1.b) -halogen;            -   4.1.c) —OR¹¹⁰ wherein R¹¹⁰ represents H or —(C₁-C₃)alkyl                which may optionally bear up to 3 substituents                independently selected from            -    4.1.c1) halogen; and            -    4.1.c5) —NR¹¹²R¹¹³ in which R¹¹² and R¹¹³ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹¹² and R¹¹³ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹¹⁴ wherein R¹¹⁴                represents H or (C₁-C₃)alkyl; or            -   4.1.d) —NR¹¹⁵R¹¹⁶ wherein            -    R¹¹⁵ represents H or —(C₁-C₃)alkyl which may optionally                bear halogen and            -    R¹¹⁶ represents H, optionally substituted phenyl, or                —(C₁-C₅)alkyl which may optionally bear up to 3                substituents independently selected from                -   4.1.d1) halogen;                -   4.1.d2) —S(O)₂CH₃;                -   4.1.d3) OR¹¹⁷ wherein R¹¹⁷ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; and                -   4.1.d4) —NR¹¹⁸R¹¹⁹ in which R¹¹⁸ and R¹¹⁹ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹¹⁸ and R¹¹⁹ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹²⁰ wherein R¹²⁰ represents H or (C₁-C₃)alkyl;        -   4.2)

wherein R¹²¹ represents —(C₁-C₃)alkyl which may optionally bear halogen;

-   -   -   -   d represents 1, 2, or 3;            -   e represents 0 or 1;            -   f represents 0, 1, or 2;

        -   4.3)

wherein R¹²³ represents —(C₁-C₃)alkyl which may optionally bear halogen;

-   -   -   -   g represents 1, 2, or 3;            -   h represents 0, 1, or 2;

        -   4.4)

wherein

-   -   -   -   R¹²⁵ represents            -    4.4.a) H;            -    4.4.b) —(C₁-C₃)alkyl which may optionally bear halogen;            -    4.4.c) —SO₂R¹²⁷ wherein R¹²⁷ represents optionally                substituted phenyl, or —(C₁-C₃)alkyl which may                optionally bear halogen;            -    4.4.d) —C(O)R¹²⁹ wherein                -   R¹²⁹ represents                -   4.4.d1) optionally substituted phenyl,                -   4.4.d2) —(C₁-C₃)alkyl which may optionally bear up                    to 3 substituents independently selected from                -    4.4.d2.1) halogen; and                -    4.4.d2.4) —OR¹³⁰ wherein R¹³⁰ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen;                -   4.4.d3) —OR¹³⁴ wherein R¹³⁴ represents (C₁-C₃)alkyl;                    or                -   4.4.d4) NR¹³⁵R¹³⁶ wherein R¹³⁵ and R¹³⁶ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen; and            -    j represents 1, 2, or 3;

        -   4.5)

wherein

-   -   -   -   X represents C or N;            -   R¹³⁸ represents            -   4.5.a) (C₁-C₄)alkyl, which may optionally bear up to 3                substituents independently selected from            -    4.5.a1) halogen;            -    4.5.a2) OR¹³⁹ wherein R¹³⁹ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; and            -    4.5.a3) —NR¹⁴⁰R¹⁴¹ in which R¹⁴⁰ and R¹⁴¹ are                independently H or —(C₁-C₃)alkyl, or R¹⁴⁰ and R¹⁴¹ may                be joined and taken together with the N atom to which                they are attached form a 5-6 membered ring which may                optionally contain a ring member selected from O, S, and                NR¹⁴² wherein R¹⁴² represents H or (C₁-C₃)alkyl;            -   4.5.b) —(C₃-C₆)cycloalkyl which may optionally bear up                to 2 substituents independently selected from            -    4.5.b1) halogen;            -   4.5.c) OR¹⁴⁴ wherein            -    R¹⁴⁴ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl;                or (C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -    4.5.c1) halogen;            -    4.5.c2) OR¹⁴⁵ wherein R¹⁴⁵ represents H or                (C₁-C₃)alkyl; and            -    4.5.c3) NR¹⁴⁶R¹⁴⁷ in which R¹⁴⁶ and R¹⁴⁷³ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁴⁶ and R¹⁴⁷ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁴⁸ wherein R¹⁴⁸                represents H or (C₁-C₃)alkyl;            -   4.5.e) —C(O)—NR¹⁵⁰R¹⁵¹ wherein            -    R¹⁵⁰ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R¹⁵¹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with                -   4.5.e1) halogen; or                -   4.5.e6) —NR¹⁵³R¹⁵⁴ in which R¹⁵³ and R¹⁵⁴ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹⁵³ and R¹⁵⁴ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹⁵⁵ wherein R¹⁵⁵ represents H or (C₁-C₃)alkyl;            -   4.5.f) —N(R¹⁵⁶)—C(O)—R¹⁵⁷ wherein            -    R¹⁵⁶ represents H or (C₁-C₃)alkyl; and            -    R¹⁵⁷ represents H, optionally substituted phenyl, or                (C₁-C₄)alkyl;            -   4.5.g) —SO₂NR¹⁶²R¹⁶³ wherein            -    R¹⁶² represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -    R¹⁶³ represents H or —(C₁-C₄)alkyl which is optionally                substituted with                -   4.5.g1) halogen; or                -   4.5.g6) —NR¹⁶⁵R¹⁶⁶ in which R¹⁶⁵ and R¹⁶⁶ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹⁶⁵ and R¹⁶⁶ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹⁶⁷ wherein R¹⁶⁷ represents H or (C₁-C₃)alkyl;            -   4.5.h) —N(R¹⁶⁸)—SO₂—R¹⁶⁹ wherein            -    R¹⁶⁸ represents H or (C_(r)—C₃)alkyl, and            -    R¹⁶⁹ represents H, optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -    4.5.h1) halogen; or            -    4.5.h4) —NR¹⁷¹R¹⁷² wherein R¹⁷¹ and R¹⁷² are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁷¹ and R¹⁷² may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁷³ wherein R¹⁷³                represents H or (C₁-C₃)alkyl;            -   4.5.i) —NR¹⁷⁴R¹⁷⁵ in which R¹⁷⁴ and R¹⁷⁵ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen or OR^(175a) wherein R^(175a) represents H                or (C₁-C₃)alkyl, or R¹⁷⁴ and R¹⁷⁵ may be joined and                taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR¹⁷⁶                wherein R¹⁷⁶ represents H or (C₁-C₃)alkyl;            -   4.5.j) halogen;            -   4.5.l) NO₂;            -   4.5.m) CN; or            -   4.5.n) a 5-6 membered aromatic heterocycle selected from                imidazole, thiazole, oxazole, pyridine, pyrazole,                pyrimidine, isoxazole, isothiazole, thiophene, and                furan; and

        -   k represents 0, 1, or 2;

        -   4.6)

wherein R¹⁷⁷ represents H or —(C₁-C₃)alkyl; and

-   -   -   -   m represents 1, 2, or 3;

        -   4.7)

wherein

-   -   -   -   n represents 1, 2, or 3; and            -   p represents 0, 1, or 2;

        -   4.8)

wherein

-   -   -   -   q represents 1, 2, or 3;

        -   4.9)

wherein

-   -   -   -   R¹⁷⁸ represents            -    4.9.a) H;            -    4.9.b) —(C₁-C₃)alkyl which may optionally bear halogen;            -    4.9.c) —SO₂R¹⁸⁰ wherein R¹⁸⁰ represents optionally                substituted phenyl or —(C₁-C₃)alkyl, which may be                substituted with halogen;            -    4.9.d) —C(O)R¹⁸² wherein R¹⁸² represents optionally                substituted phenyl or —(C₁-C₃)alkyl which may optionally                bear up to 3 substituents independently selected from                -   4.9.d1) halogen; and                -   4.9.d4) OR¹⁸³ wherein R¹⁸³ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen;            -    4.9e) —C(O)OR¹⁸⁷ wherein R¹⁸⁷ represents (C₁-C₃)alkyl;                or            -    4.9.f) —C(O)—NR¹⁸⁸R¹⁸⁹ wherein R¹⁸⁸ and R¹⁸⁹ each                independently represents H or —(C₁-C₃)alkyl which may                optionally bear halogen;            -   r represents 0, 1, or 2; and            -   s represents 0 or 1;

        -   4.10)

wherein

-   -   -   -   R¹⁹¹ represents            -    4.10.a) H;            -    4.10.b) —(C₁-C₃)alkyl which may optionally bear                halogen;            -    4.10.c) —SO₂R¹⁹³ wherein R¹⁹³ represents phenyl or                —(C₁-C₃)alkyl, both of which may be substituted with                halogen;            -    4.10.d) —C(O)R¹⁹⁴ wherein R¹⁹⁴ represents (C₁-C₃)alkyl                which may optionally bear up to 3 substituents                independently selected from                -   4.10.d1) halogen;                -   4.10.d2) phenyl; and                -   4.10.d4) OR¹⁹⁵ wherein R¹⁹⁵ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen;            -    4.10.e) —C(O)OR¹⁹⁹ wherein R¹⁹⁹ represents                (C₁-C₃)alkyl; or            -    4.10.f) —C(O)—NR²⁰⁰R²⁰¹ wherein R²⁰⁰ and R²⁰¹ each                independently represents H or —(C₁-C₃)alkyl which may                optionally bear halogen;            -   X represents O, S, S(O)₂, or NR²⁰³ wherein            -    R²⁰³ represents H or —(C₁-C₃)alkyl; and            -   t represents 0, 1, or 2;

        -   4.11) halogen; or

        -   4.12) —CN;

    -   or a pharmaceutically acceptable salt thereof.

In embodiment seven, the present invention provides a compound offormula (I)

wherein

-   -   R¹ represents        -   1.1) phenyl which may optionally bear up to 4 substituents            independently selected from the group consisting of            -   1.1.a) (C₁-C₄)alkyl, which may optionally bear up to 3                substituents independently selected from            -    1.1.a1) halogen;            -   1.1.b) —(C₃-C₆)cycloalkyl which may optionally bear up                to 2 substituents independently selected from            -    1.1.b1) halogen;            -   1.1.c) OR¹⁰ wherein            -    R¹⁰ represents H, or (C₁-C₄)alkyl which may optionally                bear up to 3 substituents independently selected from            -    1.1.c1) halogen;            -   1.1.i) —NR⁴⁰R⁴¹ in which R⁴⁰ and R⁴¹ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen;            -   1.1.j) halogen;            -   1.1.l) NO₂; and            -   1.1.m) CN;    -   or    -   R¹ represents        -   1.2) a 5-6 membered aromatic heterocycle selected from            thiazole, oxazole, pyridine, pyrazole, pyrimidine,            isoxazole, isothiazole, and thiophene; said R¹ heterocycle            optionally bearing up to 4 substituents independently            selected from the group consisting of            -   1.2.a) (C₁-C₄)alkyl, which may optionally bear up to 3                substituents independently selected from            -    1.2.a1) halogen; and            -    1.2.a4) an imidazole, thiazole, oxazole, pyridine,                pyrazole, pyrimidine, isoxazole, isothiazole, thiophene,                or furan;            -   1.2.b) —(C₃-C₆)cycloalkyl which may optionally bear up                to 2 substituents independently selected from            -    1.2.b1) halogen;            -   1.2.c) OR⁵⁰ wherein            -    R⁵⁰ represents —(C₁-C₄)alkyl which may optionally bear                up to 3 substituents independently selected from            -    1.2.c1) halogen;            -   1.2.i) —NR⁸⁰R⁸¹ in which R⁸⁰ and R⁸¹ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen;            -   1.2.j) halogen;            -   1.2.k) optionally substituted phenyl;            -   1.2.l) NO₂; and            -   1.2.m) CN;    -   R² represents halogen or —(C₁-C₅)alkyl;    -   R³ represents        -   3.1) —(C₁-C₅)alkyl which is optionally substituted with            -   3.1.a) -halogen;            -   3.1.d) —CN; or            -   3.1.e) —OR⁸³ wherein R⁸³ represents H or —(C₁-C₃)alkyl                which may optionally bear up to 3 substituents                independently selected from            -    3.1.e1) halogen;            -   3.1.g) —NR⁸⁹R⁹⁰ wherein            -    R⁸⁹ represents H; and            -    R⁹⁰ represents —(C₁-C₄)alkyl which is optionally                substituted with —OR⁹¹ wherein R⁹¹ represents H or                (C₁-C₃)alkyl;        -   3.2)

wherein

-   -   -   -   R⁹⁶ represents            -   3.2.b) —(C₃-C₅)cycloalkyl which may optionally bear                halogen; or            -   3.2.c) —(C₁-C₅)alkyl;

        -   3.3)

wherein R¹⁰¹ represents H or —(C₁-C₅)alkyl;

-   -   -   3.4)

wherein

-   -   -   -   R¹⁰² represents H or —(C₁-C₃)alkyl which may optionally                bear halogen; and            -   R¹⁰³ represents H or —(C₁-C₅)alkyl which may optionally                bear up to 3 substituents independently selected from            -    3.4.a) halogen;

        -   3.6) a 5-6 membered aromatic heterocycle selected from            imidazole, thiazole, oxazole, pyrazole, isoxazole, and            isothiazole;

        -   3.7) halogen; or

        -   3.8) —CN;

    -   R⁴ represents        -   4.1) —(C₁-C₅)alkyl which is optionally substituted with            -   4.1.b) -halogen;            -   4.1.c) —OR¹¹⁰ wherein R¹¹⁰ represents H or —(C₁-C₃)alkyl                which may optionally bear up to 3 substituents                independently selected from            -    4.1.c1) halogen; or            -   4.1.d) —NR¹¹⁵R¹¹⁶ wherein            -    R¹¹⁵ represents H or —(C₁-C₃)alkyl which may optionally                bear halogen, and            -    R¹¹⁶ represents H, optionally substituted phenyl, or                —(C₁-C₅)alkyl which may optionally bear up to 3                substituents independently selected from                -   4.1.d1) halogen;                -   4.1.d3) OR¹¹⁷ wherein R¹¹⁷ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; and                -   4.1.d4) —NR¹¹⁸R¹¹⁹ in which R¹¹⁸ and R¹¹⁹ are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹¹⁸ and R¹¹⁹ may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹²⁰ wherein R¹²⁰ represents H or (C₁-C₃)alkyl;        -   4.2)

wherein R¹²¹ represents —(C₁-C₃)alkyl which may optionally bear halogen;

-   -   -   -   d represents 1, 2, or 3;            -   e represents 0 or 1;            -   f represents 0, 1, or 2;

        -   4.3)

wherein R¹²³ represents —(C₁-C₃)alkyl which may optionally bear halogen;

-   -   -   -   g represents 1, 2, or 3;            -   h represents 0, 1, or 2;

        -   4.4)

wherein

-   -   -   -   R¹²⁵ represents            -    4.4.a) H;            -    4.4.b) —(C₁-C₃)alkyl;            -    4.4.c) —SO₂R¹²⁷ wherein R¹²⁷ represents optionally                substituted phenyl, or —(C₁-C₃)alkyl;            -    4.4.d) —C(O)R¹²⁹ wherein                -   R¹²⁹ represents                -   4.4.d2) —(C₁-C₃)alkyl which may optionally bear                -    4.4.d2.4) —OR¹³⁰ wherein R¹³⁰ represents H or                    (C₁-C₃)alkyl;                -   4.4.d3) —OR¹³⁴ wherein R¹³⁴ represents (C₁-C₃)alkyl;                    or                -   4.4.d4) NR¹³⁵R¹³⁶ wherein R¹³⁵ and R¹³⁶ are                    independently H or —(C₁-C₃); and            -    j represents 1, 2, or 3;

        -   4.5)

wherein

-   -   -   -   X represents C or N;            -   R¹³⁸ represents            -   4.5.a) (C₁-C₄)alkyl, which may optionally bear up to 3                substituents independently selected from            -    4.5.a1) halogen;            -   4.5.b) —(C₃-C₆)cycloalkyl which may optionally bear up                to 2 substituents independently selected from            -    4.5.b1) halogen;            -   4.5.c) OR¹⁴⁴ wherein            -    R¹⁴⁴ represents H, or (C₁-C₄)alkyl which may optionally                bear up to 3 substituents independently selected from            -    4.5.c1) halogen;            -   4.5.i) —NR¹⁷⁴R¹⁷⁵ in which R¹⁷⁴ and R¹⁷⁵ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen;            -   4.5.j) halogen;            -   4.5.l) NO₂; or            -   4.5.m) CN; and

        -   k represents 0, 1, or 2;

        -   4.6)

wherein

-   -   -   -   R¹⁷⁷ represents H or —(C₁-C₃)alkyl; and            -   m represents 1, 2, or 3;

        -   4.7)

wherein

-   -   -   -   n represents 1, 2, or 3; and            -   p represents 0, 1, or 2;

        -   4.8)

wherein

-   -   -   -   q represents 1, 2, or 3;

        -   4.9)

wherein

-   -   -   -   R¹⁷⁸ represents            -    4.9.a) H;            -    4.9.b) —(C₁-C₃)alkyl;            -    4.9.c) —SO₂R¹⁸⁰ wherein R¹⁸⁰ represents —(C₁-C₃)alkyl;            -    4.9.d) —C(O)R¹⁸² wherein R¹⁸² represents —(C₁-C₃)alkyl                which may optionally bear up to 3 substituents                independently selected from                -   4.9.d4) OR¹⁸³ wherein R¹⁸³ represents H or                    (C₁-C₃)alkyl;            -    4.9e) —C(O)OR¹⁸⁷ wherein R¹⁸⁷ represents (C₁-C₃)alkyl;                or            -    4.9.f) —C(O)—NR¹⁸⁸R¹⁸⁹ wherein R¹⁸⁸ and R¹⁸⁹ each                independently represents H or —(C₁-C₃)alkyl;            -   r represents 0, 1, or 2; and            -   s represents 0 or 1;

        -   4.10)

wherein

-   -   -   -   R¹⁹¹ represents            -    4.10.a) H;            -    4.10.b) —(C₁-C₃)alkyl;            -    4.10c) —SO₂R¹⁹³ wherein R¹⁹³ represents —(C₁-C₃)alkyl;            -    4.10.d) —C(O)R¹⁹⁴ wherein R¹⁹⁴ represents (C₁-C₃)alkyl                which may optionally bear up to 3 substituents                independently selected from                -   4.10.d4) OR¹⁹⁵ wherein R¹⁹⁵ represents H or                    (C₁-C₃)alkyl;            -    4.10.e) —C(O)OR¹⁹⁹ wherein R¹⁹⁹ represents                (C₁-C₃)alkyl; or            -    4.10.f) —C(O)—NR²⁰⁰R²⁰¹ wherein R²⁰⁰ and R²⁰¹ each                independently represents H or —(C₁-C₃)alkyl;            -   X represents O, S, S(O)₂, or NR²⁰³ wherein            -    R²⁰³ represents H or —(C₁-C₃)alkyl; and            -   t represents 0, 1, or 2;

        -   4.11) halogen; or

        -   4.12) —CN;

    -   or a pharmaceutically acceptable salt thereof.

An intermediate which is useful in the synthesis of the compounds of theinvention has the general formula shown below as Q1

wherein

-   -   R represents H or (C₁-C₅)alkyl; and    -   R² represents halogen; —(C₁-C₅)alkyl which may optionally bear        halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen.

A second intermediate which is useful in the synthesis of the compoundsof the invention has the general formula shown below as Q2

wherein

-   -   G³ represents halogen, (C₁-C₅)alkyl, —CN, —C(O)O(C₁-C₅)alkyl, or        —C(O)H.        Definitions

Where the plural form of the word compounds, salts, polymorphs,hydrates, solvates and the like, is used herein, this is taken to meanalso a single compound, salt, polymorph, isomer, hydrate, solvate or thelike.

The compounds of this invention may contain one or more asymmetriccenters, depending upon the location and nature of the varioussubstituents desired. Asymmetric carbon atoms may be present in the (R)or (S) configuration, resulting in racemic mixtures in the case of asingle asymmetric center, and diastereomeric mixtures in the case ofmultiple asymmetric centers. In certain instances, asymmetry may also bepresent due to restricted rotation about a given bond, for example, thecentral bond adjoining two substituted aromatic rings of the specifiedcompounds. Substituents on a ring may also be present in either cis ortrans form. It is intended that all such configurations (includingenantiomers and diastereomers), are included within the scope of thepresent invention. Preferred compounds are those which produce the moredesirable biological activity. Separated, pure or partially purifiedisomers and stereoisomers or racemic or diastereomeric mixtures of thecompounds of this invention are also included within the scope of thepresent invention. The purification and the separation of such materialscan be accomplished by standard techniques known in the art.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, for example, by theformation of diastereoisomeric salts using an optically active acid orbase or formation of covalent diastereomers. Examples of appropriateacids are tartaric, diacetyltartaric, ditoluoyltartaric andcamphorsulfonic acid. Mixtures of diastereoisomers can be separated intotheir individual diastereomers on the basis of their physical and/orchemical differences by methods known in the art, for example, bychromatography or fractional crystallization. The optically active basesor acids are then liberated from the separated diastereomeric salts. Adifferent process for separation of optical isomers involves the use ofchiral chromatography (e.g., chiral HPLC columns), with or withoutconventional derivitization, optimally chosen to maximize the separationof the enantiomers. Suitable chiral HPLC columns are manufactured byDiacel, e.g., Chiracel OD and Chiracel OJ among many others, allroutinely selectable. Enzymatic separations, with or withoutderivitization, are also useful. The optically active compounds of thisinvention can likewise be obtained by chiral syntheses utilizingoptically active starting materials.

The present invention also relates to useful forms of the compounds asdisclosed herein, such as pharmaceutically acceptable salts,co-precipitates, metabolites, hydrates, solvates and prodrugs of all thecompounds of examples. The term “pharmaceutically acceptable salt”refers to a relatively non-toxic, inorganic or organic acid additionsalt of a compound of the present invention. For example, see S. M.Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.Pharmaceutically acceptable salts include those obtained by reacting themain compound, functioning as a base, with an inorganic or organic acidto form a salt, for example, salts of hydrochloric acid, sulfuric acid,phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalicacid, maleic acid, succinic acid and citric acid. Pharmaceuticallyacceptable salts also include those in which the main compound functionsas an acid and is reacted with an appropriate base to form, e.g.,sodium, potassium, calcium, magnesium, ammonium, and chorine salts.Those skilled in the art will further recognize that acid addition saltsof the claimed compounds may be prepared by reaction of the compoundswith the appropriate inorganic or organic acid via any of a number ofknown methods. Alternatively, alkali and alkaline earth metal salts ofacidic compounds of the invention are prepared by reacting the compoundsof the invention with the appropriate base via a variety of knownmethods.

Representative salts of the compounds of this invention include theconventional non-toxic salts and the quaternary ammonium salts which areformed, for example, from inorganic or organic acids or bases by meanswell known in the art. For example, such acid addition salts includeacetate, adipate, alginate, ascorbate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate,maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate,nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate,tartrate, thiocyanate, tosylate, and undecanoate.

Base salts include alkali metal salts such as potassium and sodiumsalts, alkaline earth metal salts such as calcium and magnesium salts,and ammonium salts with organic bases such as dicyclohexylamine andN-methyl-D-glutamine. Additionally, basic nitrogen containing groups maybe quaternized with such agents as lower alkyl halides such as methyl,ethyl, propyl, and butyl chlorides, bromides and iodides; dialkylsulfates like dimethyl, diethyl, and dibutyl sulfate; and diamylsulfates, long chain halides such as decyl, lauryl, myristyl andstrearyl chlorides, bromides and iodides, aralkyl halides like benzyland phenethyl bromides and others.

The term “solvates” for the purposes of the invention are those forms ofthe compounds that coordinate with solvent molecules to form a complexin the solid or liquid state. Hydrates are a specific form of solvates,wherein the solvent is water.

The term “alkyl” refers to a straight-chain or branched saturatedhydrocarbon radical having generally 1 to 6, 1 to 4 or 1 to 3 carbonatoms, illustratively representing methyl, ethyl, n-propyl, isopropyl,tert-butyl, n-pentyl and n-hexyl.

The term “cycloalkyl” refers to saturated carbocyclic groups. Preferredcycloalkyl groups include C₃-C₆ rings, illustratively representingcyclopropyl, cyclopentyl, and cyclohexyl.

The term “alkoxy” refers to a straight-chain or branched hydrocarbonradical having 1 to 6, 1 to 4 or 1 to 3 carbon atoms and bound via anoxygen atom, illustratively representing methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy.The terms “alkoxy” and “alkyloxy” are often used synonymously.

The term “alkylamino” refers to an amino radical having one or two(independently selected) alkyl substituents, illustratively representingmethylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino,n-pentylamino, n-hexylamino, N,N-dimethylamino, N,N-diethylamino,N-ethyl-N-methylamino, N-methyl-N-n-propylamino,N-isopropyl-N-n-propylamino, N-t-butyl-N-methylamino,N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino.

The term “alkylaminocarbonyl” refers to an alkylaminocarbonyl radicalhaving one or two (independently selected) alkyl substituents,illustratively representing methylaminocarbonyl, ethylaminocarbonyl,n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylamino-carbonyl,n-pentylaminocarbonyl, n-hexylaminocarbonyl, N,N-dimethylaminocarbonyl,N,N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl,N-methyl-N-n-propylaminocarbonyl, N-isopropyl-N-n-propylaminocarbonyl,N-t-butyl-N-methylaminocarbonyl, N-ethyl-N-n-pentylamino-carbonyl andN-n-hexyl-N-methylaminocarbonyl.

The term “alkylaminosulfonyl” refers to an aminosulfonyl radical havingone or two (independently selected) alkyl substitutents on the aminomoiety, illustratively representing methylaminosulfonyl,ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl,tert-butylaminosulfonyl, n-pentylaminosulfonyl, n-hexyl-aminosulfonyl,N,N-dimethylaminosulfonyl, N,N-diethylaminosulfonyl,N-ethyl-N-methylaminosulfonyl, N-methyl-N-n-propylaminosulfonyl,N-isopropyl-N-n-propylaminosulfonyl, N-t-butyl-N-methylaminosulfonyl,N-ethyl-N-n-pentylaminosulfonyl and N-n-hexyl-N-methylaminosulfonyl.

The term “alkylsulfonylamino” refers to a sulfonylamino radical havingan alkyl substitutent on the sulfonylamino moiety, illustrativelyrepresenting methylsulfonylamino, ethylsulfonylamino,n-propylsulfonylamino, isopropylsulfonylamino, tert-butyl-sulfonylamino,n-pentylsulfonylamino and n-hexylsulfonylamino.

The term “alkoxycarbonyl” refers to a carbonyl radical being substitutedwith an alkoxy radical, illustratively representing methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl,tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

The term “alkoxycarbonylamino” refers to a carbonylamino radical beingsubstituted with an alkoxy radical on the carbonyl moiety,illustratively representing methoxycarbonylamino, ethoxycarbonylamino,n-propoxycarbonylamino, isopropoxycarbonylamino,tert-butoxy-carbonylamino, n-pentoxycarbonylamino andn-hexoxycarbonylamino.

The term “heteroaryl” refers to a mono- or bicyclic radical having 5 to10 or 5 or 6 ring atoms and up to 4 hetero atoms selected from the groupconsisting of nitrogen, oxygen and sulfur, which is aromatic at least inone ring. It can be attached via a ring carbon atom or a ring nitrogenatom. If it represents a bicycle, wherein one ring is aromatic and theother one is not, it can be attached at either ring. Illustrativeexamples of such groups are the thiophene, furan, pyrrole, thiazole,oxazole, imidazole, pyridine, pyrimidine, pyridazine, indole, indazole,benzofuran, benzothiophene, quinoline and isoquinoline groups.

Language reciting a 5-6 membered aromatic heterocycle containing up to 3heteroatoms independently selected from the group consisting of N, O,and S is meant to refer to aromatic heterocycles such as furan,thiophene, pyrrole, pyrazole, triazole, isoxazole, oxazole, thiazole,isothiazole, imidaxole, an oxadiazole, 1,3,2-dioxazole,1,2,5-oxathiazole, 1,2-pyrone, 1,4-pyrone, pyridine, pyridazine,pyrimidine, pyrazine, a triazine, o- and p-isoxazines,1,2,5-oxathiazine, 1,2,4-oxadiazine, and the like.

Language reciting a bicyclic heterocycle of 8-10 ring members in whichat least one ring is aromatic and contains up to 3 moietiesindependently selected from the group consisting of N, N→O, O, and S,and any non-aromatic ring of said bicyclic heterocycle optionallycontains up to three moieties independently selected from the groupconsisting of O, S, S(O), S(O)₂, and NR, is meant to refer to bicyclicheterocycles in which at least one ring is a 5-6-membered aromaticheterocycle as discussed above, which is fused to a second ring whichmay be aromatic or nonaromatic. Where this second ring is aromatic, itmay also optionally contain up to 3 moieties independently selected fromthe group consisting of N, N→O, O, and S, and where this second ring isnonaromatic, it may optionally contain up to three moietiesindependently selected from O, S, S(O), S(O)₂, and NR.

The term “heterocyclyl” refers to a saturated or partially unsaturatedmono- or bicyclic heterocyclic ring which contains 3 to 8 or 5 to 6 ringatoms and 1 to 3 heteroatoms or hetero groups selected independentlyfrom the group consisting of nitrogen, oxygen and sulfur, CO, SO andSO₂, such as tetrahydrofuran-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,pyrrolinyl, piperidinyl, morpholinyl, or perhydroazepinyl. It can beattached via a ring carbon atom or a ring nitrogen atom.

The terms “halo” and “halogen” refer to fluorine, chlorine, bromine oriodine.

A bicyclic carbocycle of 9-10 ring members in which at least one ring isaromatic is a compound such as indene, isoindene, andtetrahydronaphthalene.

Language stating that an alkyl or alkoxy group may optionally bearhalogen or may be substituted with halogen means that the group may bearone or more halogens, up to perhalo.

Language reciting that in a group —NRR, the two R groups may be joinedand taken together with the N atom to which they are attached form a 5-6membered ring which may optionally contain a ring member selected fromO, S, and NR^(x) wherein R^(x) represents H or (C₁-C₃)alkyl, is meant toindicate formation of groups such as pyrrolidine, imidazolidine,piperidine piperazine, morpholine, thiomorpholine, and the like.

Language indicating that two substituent groups of a tertiary aminomoiety may be joined and taken together with the N to which they areattached form an aromatic or nonaromatic 5-6 membered ring which mayoptionally contain a ring member selected from O, S, and NR is meant toindicate the possibility of forming 5-6-membered N-containingheterocycles such as pyrrole, pyrazole, piperazine, morpholine,piperidine, imidazole, pyrrolidine, imidazolidene, and the like.

When NR is indicated as being part of a heterocycle, this means that theN atom is the ring member and R is a substituent.

Language reciting a 5-6 membered heteroaromatic containing up to twoheteroatoms selected from O, S, and N is meant to refer to groups suchas furan, thiophene, pyrrole, pyrazole, oxazole, isoxazole, thiazole,isothiazole, imidazole, pyridine, pyridazine, pyrimidine, pyrazine,isoxazine, and the like.

The term “aryl” refers to a mono- to tricyclic carbocyclic radical,which is aromatic at least in one ring, having generally 6 to 14 carbonatoms, illustratively representing phenyl, naphthyl and phenanthrenyl.

The term “substituted phenyl” refers to an phenyl radical having one ormore (but typically not more than three) groups independently selectedfrom halogen; alkyl such as (C₁-C₃)alkyl; alkoxy such as O(C₁-C₃)alkyl;CN; cycloalkyl; heteroaryl; heterocyclyl; amino; alkylamino such asmono- or di-(C₁-C₃)alkylamino; acylamino wherein for example the acylgroup is —C(O)(C₁-C₃)alkyl or —C(O)phenyl alkoxycarbonyl; CN; NO₂;alkynyl; alkenyl; C(O)NH₂; C(O)NH(C₁-C₃)alkyl; C(O)N((C₁-C₃)alkyl)₂;C(O)NH-phenyl; —NHC(O)NH₂; alkylaminosulfonyl; alkylsulfonylamino; andalkoxycarbonylamino, and in these groups, alkyl and phenyl groups may befurther substituted with halogen.

Language stating that phenyl may be optionally substituted with halogenmeans that the phenyl group optionally may bear one or more substituentsindependently selected from fluorine, chlorine, bromine and iodine, upto a maximum of perhalo, but typically not more than three such groups.

Language stating that a cycloalkyl group may optionally bear halogen oralkoxy is meant to indicate that the cycloalkyl group may be bear one ormore halogen substituents, up to perhalo, and/or it may bear one or morealkoxy groups, generally up to a maximum of three.

The skilled in the art understand that when two heteroatoms are attachedto a single aliphatic carbon atom, the resulting material is usually notstable. Accordingly, in this invention, when an aliphatic group bearstwo heteroatom-containing substituents (such as amino and alkoxy, forexample) in which the heteroatoms are joined to the aliphatic group,such heteroatom-containing substituents will generally need to belocated on different carbon atoms of the aliphatic material.

A wavy line across the end of a line which indicates a chemical bondextending from a chemical substructure or functional group means thatthe substructure or group is attached to the remainder of the moleculevia that bond.

A carbonyl group is indicated as C═O in a chemical structure orsubstructure, or by C(O) in a typed formula.

In naming a multiunit functional group by listing the constituent units,the terminal unit is recited first, then the adjacent unit is recited,etc. An example of this style of nomenclature would be “alkylphenyl”,which connotes an alkyl group located on a phenyl group, which is inturn connected to the remainder of the molecule. Conversely, the term“phenylalkyl” would connote a phenyl group located on an alkyl groupwhich is in turn connected to the remainder of the molecule. Anotherexample would be “cycloalkylalkyl”, which connotes a cycloalkyl groupconnected to an alkyl group which is in turn connected to the remainderof the molecule.

In this document, for the sake of simplicity, the names of substituentgroups are generally (but not always) given as names of the parentcompounds rather than using nomenclature which indicates their status assubstituents. Thus, for example, if a substituent in a compound of theinvention were a pyridine ring, it would generally be termed a“pyridine” substituent rather than a being referred to as a “pyridyl”group. Where the nomenclature indicating status as a substituent is notemployed, and a substituent is named in terms of its parent, its statusas a substituent will be clear from the context.

Salts of the compounds identified herein can be obtained by isolatingthe compounds as hydrochloride salts, prepared by treatment of the freebase with anhydrous HCl in a suitable solvent such as THF. Generally, adesired salt of a compound of this invention can be prepared in situduring the final isolation and purification of a compound by means wellknown in the art. Or, a desired salt can be prepared by separatelyreacting the purified compound in its free base form with a suitableorganic or inorganic acid and isolating the salt thus formed. Thesemethods are conventional and would be readily apparent to one skilled inthe art.

If used as active compounds, the compounds according to the inventionare preferably isolated in more or less pure form, that is more or lessfree from residues from the synthetic procedure. The degree of puritycan be determined by methods known to the chemist or pharmacist (seeespecially Remington's Pharmaceutical Sciences, 18^(th) ed. 1990, MackPublishing Group, Enolo). Preferably the compounds are greater than 99%pure (w/w), while purities of greater than 95%, 90% or 85% can beemployed if necessary.

Throughout this document, for the sake of simplicity, the use ofsingular language is given preference over plural language, but isgenerally meant to include the plural language if not otherwise stated.E.g., the expression “A method of treating a disease in a patient,comprising administering to a patient an effective amount of a compoundof claim 1” is meant to include the simultaneous treatment of more thanone disease as well as the administration of more than one compound ofclaim 1.

The compounds according to the invention exhibit an unforeseeable,useful pharmacological and pharmacokinetic activity spectrum. They aretherefore suitable for use as medicaments for the treatment and/orprophylaxis of disorders in humans and animals.

Pharmaceutical Compositions of the Compounds of the Invention

This invention also relates to pharmaceutical compositions containingone or more compounds of the present invention. These compositions canbe utilized to achieve the desired pharmacological effect byadministration to a patient in need thereof. A patient, for the purposeof this invention, is a mammal, including a human, in need of treatmentfor the particular condition or disease. Therefore, the presentinvention includes pharmaceutical compositions that are comprised of apharmaceutically acceptable carrier and a pharmaceutically effectiveamount of a compound, or salt thereof, of the present invention. Apharmaceutically acceptable carrier is preferably a carrier that isrelatively non-toxic and innocuous to a patient at concentrationsconsistent with effective activity of the active ingredient so that anyside effects ascribable to the carrier do not vitiate the beneficialeffects of the active ingredient. A pharmaceutically effective amount ofcompound is preferably that amount which produces a result or exerts aninfluence on the particular condition being treated. The compounds ofthe present invention can be administered withpharmaceutically-acceptable carriers well known in the art using anyeffective conventional dosage unit forms, including immediate, slow andtimed release preparations, orally, parenterally, topically, nasally,ophthalmically, optically, sublingually, rectally, vaginally, and thelike.

For oral administration, the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, lozenges,melts, powders, solutions, suspensions, or emulsions, and may beprepared according to methods known to the art for the manufacture ofpharmaceutical compositions. The solid unit dosage forms can be acapsule that can be of the ordinary hard- or soft-shelled gelatin typecontaining, for example, surfactants, lubricants, and inert fillers suchas lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tabletedwith conventional tablet bases such as lactose, sucrose and cornstarchin combination with binders such as acacia, corn starch or gelatin,disintegrating agents intended to assist the break-up and dissolution ofthe tablet following administration such as potato starch, alginic acid,corn starch, and guar gum, gum tragacanth, acacia, lubricants intendedto improve the flow of tablet granulation and to prevent the adhesion oftablet material to the surfaces of the tablet dies and punches, forexample talc, stearic acid, or magnesium, calcium or zinc stearate,dyes, coloring agents, and flavoring agents such as peppermint, oil ofwintergreen, or cherry flavoring, intended to enhance the aestheticqualities of the tablets and make them more acceptable to the patient.Suitable excipients for use in oral liquid dosage forms includedicalcium phosphate and diluents such as water and alcohols, forexample, ethanol, benzyl alcohol, and polyethylene alcohols, either withor without the addition of a pharmaceutically acceptable surfactant,suspending agent or emulsifying agent. Various other materials may bepresent as coatings or to otherwise modify the physical form of thedosage unit. For instance tablets, pills or capsules may be coated withshellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of anaqueous suspension. They provide the active ingredient in admixture witha dispersing or wetting agent, a suspending agent and one or morepreservatives. Suitable dispersing or wetting agents and suspendingagents are exemplified by those already mentioned above. Additionalexcipients, for example those sweetening, flavoring and coloring agentsdescribed above, may also be present.

The pharmaceutical compositions of this invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oilsuch as liquid paraffin or a mixture of vegetable oils. Suitableemulsifying agents may be (1) naturally occurring gums such as gumacacia and gum tragacanth, (2) naturally occurring phosphatides such assoy bean and lecithin, (3) esters or partial esters derived form fattyacids and hexitol anhydrides, for example, sorbitan monooleate, (4)condensation products of said partial esters with ethylene oxide, forexample, polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavoring agents.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil such as, for example, arachis oil, olive oil, sesameoil or coconut oil, or in a mineral oil such as liquid paraffin. Theoily suspensions may contain a thickening agent such as, for example,beeswax, hard paraffin, or cetyl alcohol. The suspensions may alsocontain one or more preservatives, for example, ethyl or n-propylp-hydroxybenzoate; one or more coloring agents; one or more flavoringagents; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, and preservative, such asmethyl and propyl parabens and flavoring and coloring agents.

The compounds of this invention may also be administered parenterally,that is, subcutaneously, intravenously, intraocularly, intrasynovially,intramuscularly, or interperitoneally, as injectable dosages of thecompound in preferably a physiologically acceptable diluent with apharmaceutical carrier which can be a sterile liquid or mixture ofliquids such as water, saline, aqueous dextrose and related sugarsolutions, an alcohol such as ethanol, isopropanol, or hexadecylalcohol, glycols such as propylene glycol or polyethylene glycol,glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol, etherssuch as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acidester or, a fatty acid glyceride, or an acetylated fatty acid glyceride,with or without the addition of a pharmaceutically acceptable surfactantsuch as a soap or a detergent, suspending agent such as pectin,carbomers, methycellulose, hydroxypropylmethylcellulose, orcarboxymethylcellulose, or emulsifying agent and other pharmaceuticaladjuvants.

Illustrative of oils which can be used in the parenteral formulations ofthis invention are those of petroleum, animal, vegetable, or syntheticorigin, for example, peanut oil, soybean oil, sesame oil, cottonseedoil, corn oil, olive oil, petrolatum and mineral oil. Suitable fattyacids include oleic acid, stearic acid, isostearic acid and myristicacid. Suitable fatty acid esters are, for example, ethyl oleate andisopropyl myristate. Suitable soaps include fatty acid alkali metal,ammonium, and triethanolamine salts and suitable detergents includecationic detergents, for example dimethyl dialkyl ammonium halides,alkyl pyridinium halides, and alkylamine acetates; anionic detergents,for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether,and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents,for example, fatty amine oxides, fatty acid alkanolamides, andpoly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxidecopolymers; and amphoteric detergents, for example,alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammoniumsalts, as well as mixtures.

The parenteral compositions of this invention will typically containfrom about 0.5% to about 25% by weight of the active ingredient insolution. Preservatives and buffers may also be used advantageously. Inorder to minimize or eliminate irritation at the site of injection, suchcompositions may contain a non-ionic surfactant having ahydrophile-lipophile balance (HLB) preferably of from about 12 to about17. The quantity of surfactant in such formulation preferably rangesfrom about 5% to about 15% by weight. The surfactant can be a singlecomponent having the above HLB or can be a mixture of two or morecomponents having the desired HLB.

Illustrative of surfactants used in parenteral formulations are theclass of polyethylene sorbitan fatty acid esters, for example, sorbitanmonooleate and the high molecular weight adducts of ethylene oxide witha hydrophobic base, formed by the condensation of propylene oxide withpropylene glycol.

The pharmaceutical compositions may be in the form of sterile injectableaqueous suspensions. Such suspensions may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents such as, for example, sodium carboxymethylcellulose,methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents which may be a naturally occurring phosphatide such aslecithin, a condensation product of an alkylene oxide with a fatty acid,for example, polyoxyethylene stearate, a condensation product ofethylene oxide with a long chain aliphatic alcohol, for example,heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxidewith a partial ester derived form a fatty acid and a hexitol such aspolyoxyethylene sorbitol monooleate, or a condensation product of anethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent. Diluents and solvents that may be employed are, for example,water, Ringer's solution, isotonic sodium chloride solutions andisotonic glucose solutions. In addition, sterile fixed oils areconventionally employed as solvents or suspending media. For thispurpose, any bland, fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid can be usedin the preparation of injectables.

A composition of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritationexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are, for example, cocoa butter and polyethyleneglycol.

Another formulation employed in the methods of the present inventionemploys transdermal delivery devices (“patches”). Such transdermalpatches may be used to provide continuous or discontinuous infusion ofthe compounds of the present invention in controlled amounts. Theconstruction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art (see, e.g., U.S. Pat. No.5,023,252, issued Jun. 11, 1991, incorporated herein by reference). Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents.

Controlled release formulations for parenteral administration includeliposomal, polymeric microsphere and polymeric gel formulations that areknown in the art.

It may be desirable or necessary to introduce the pharmaceuticalcomposition to the patient via a mechanical delivery device. Theconstruction and use of mechanical delivery devices for the delivery ofpharmaceutical agents is well known in the art. Direct techniques for,for example, administering a drug directly to the brain usually involveplacement of a drug delivery catheter into the patient's ventricularsystem to bypass the blood-brain barrier. One such implantable deliverysystem, used for the transport of agents to specific anatomical regionsof the body, is described in U.S. Pat. No. 5,011,472, issued Apr. 30,1991.

The compositions of the invention can also contain other conventionalpharmaceutically acceptable compounding ingredients, generally referredto as carriers or diluents, as necessary or desired. Conventionalprocedures for preparing such compositions in appropriate dosage formscan be utilized. Such ingredients and procedures include those describedin the following references, each of which is incorporated herein byreference: Powell, M. F. et al, “Compendium of Excipients for ParenteralFormulations” PDA Journal of Pharmaceutical Science & Technology 1998,52 (5), 238-311; Strickley, R. G “Parenteral Formulations of SmallMolecule Therapeutics Marketed in the United States (1999)-Part-1” PDAJournal of Pharmaceutical Science & Technology 1999, 53 (6), 324-349;and Nema, S. et al, “Excipients and Their Use in Injectable Products”PDA Journal of Pharmaceutical Science & Technology 1997, 51 (4),166-171.

Commonly used pharmaceutical ingredients that can be used as appropriateto formulate the composition for its intended route of administrationinclude:

-   acidifying agents (examples include but are not limited to acetic    acid, citric acid, fumaric acid, hydrochloric acid, nitric acid);-   alkalinizing agents (examples include but are not limited to ammonia    solution, ammonium carbonate, diethanolamine, monoethanolamine,    potassium hydroxide, sodium borate, sodium carbonate, sodium    hydroxide, triethanolamine, trolamine);-   adsorbents (examples include but are not limited to powdered    cellulose and activated charcoal);-   aerosol propellants (examples include but are not limited to carbon    dioxide, CCl₂F₂, F₂ClC—CClF₂ and CClF₃)-   air displacement agents (examples include but are not limited to    nitrogen and argon);-   antifungal preservatives (examples include but are not limited to    benzoic acid, butylparaben, ethylparaben, methylparaben,    propylparaben, sodium benzoate);-   antimicrobial preservatives (examples include but are not limited to    benzalkonium chloride, benzethonium chloride, benzyl alcohol,    cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl    alcohol, phenylmercuric nitrate and thimerosal);-   antioxidants (examples include but are not limited to ascorbic acid,    ascorbyl palmitate, butylated hydroxyanisole, butylated    hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl    gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde    sulfoxylate, sodium metabisulfite);-   binding materials (examples include but are not limited to block    polymers, natural and synthetic rubber, polyacrylates,    polyurethanes, silicones, polysiloxanes and styrene-butadiene    copolymers);-   buffering agents (examples include but are not limited to potassium    metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate    anhydrous and sodium citrate dihydrate)-   carrying agents (examples include but are not limited to acacia    syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup,    orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil,    bacteriostatic sodium chloride injection and bacteriostatic water    for injection)-   chelating agents (examples include but are not limited to edetate    disodium and edetic acid)-   colorants (examples include but are not limited to FD&C Red No. 3,    FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No.    5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red);-   clarifying agents (examples include but are not limited to    bentonite);-   emulsifying agents (examples include but are not limited to acacia,    cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin,    sorbitan monooleate, polyoxyethylene 50 monostearate);-   encapsulating agents (examples include but are not limited to    gelatin and cellulose acetate phthalate)-   flavorants (examples include but are not limited to anise oil,    cinnamon oil, cocoa, menthol, orange oil, peppermint oil and    vanillin);-   humectants (examples include but are not limited to glycerol,    propylene glycol and sorbitol);-   levigating agents (examples include but are not limited to mineral    oil and glycerin);-   oils (examples include but are not limited to arachis oil, mineral    oil, olive oil, peanut oil, sesame oil and vegetable oil);-   ointment bases (examples include but are not limited to lanolin,    hydrophilic ointment, polyethylene glycol ointment, petrolatum,    hydrophilic petrolatum, white ointment, yellow ointment, and rose    water ointment);-   penetration enhancers (transdermal delivery) (examples include but    are not limited to monohydroxy or polyhydroxy alcohols, mono- or    polyvalent alcohols, saturated or unsaturated fatty alcohols,    saturated or unsaturated fatty esters, saturated or unsaturated    dicarboxylic acids, essential oils, phosphatidyl derivatives,    cephalin, terpenes, amides, ethers, ketones and ureas)-   plasticizers (examples include but are not limited to diethyl    phthalate and glycerol);-   solvents (examples include but are not limited to ethanol, corn oil,    cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid,    peanut oil, purified water, water for injection, sterile water for    injection and sterile water for irrigation);-   stiffening agents (examples include but are not limited to cetyl    alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl    alcohol, white wax and yellow wax);-   suppository bases (examples include but are not limited to cocoa    butter and polyethylene glycols (mixtures));-   surfactants (examples include but are not limited to benzalkonium    chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl    sulfate and sorbitan mono-palmitate);-   suspending agents (examples include but are not limited to agar,    bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl    cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,    kaolin, methylcellulose, tragacanth and veegum);-   sweetening agents (examples include but are not limited to    aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin    sodium, sorbitol and sucrose);-   tablet anti-adherents (examples include but are not limited to    magnesium stearate and talc);-   tablet binders (examples include but are not limited to acacia,    alginic acid, carboxymethylcellulose sodium, compressible sugar,    ethylcellulose, gelatin, liquid glucose, methylcellulose,    non-crosslinked polyvinyl pyrrolidone, and pregelatinized starch);-   tablet and capsule diluents (examples include but are not limited to    dibasic calcium phosphate, kaolin, lactose, mannitol,    microcrystalline cellulose, powdered cellulose, precipitated calcium    carbonate, sodium carbonate, sodium phosphate, sorbitol and starch);-   tablet coating agents (examples include but are not limited to    liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose,    hydroxypropyl methylcellulose, methylcellulose, ethylcellulose,    cellulose acetate phthalate and shellac);-   tablet direct compression excipients (examples include but are not    limited to dibasic calcium phosphate);-   tablet disintegrants (examples include but are not limited to    alginic acid, carboxymethylcellulose calcium, microcrystalline    cellulose, polacrillin potassium, cross-linked polyvinylpyrrolidone,    sodium alginate, sodium starch glycollate and starch);-   tablet glidants (examples include but are not limited to colloidal    silica, corn starch and talc);-   tablet lubricants (examples include but are not limited to calcium    stearate, magnesium stearate, mineral oil, stearic acid and zinc    stearate);-   tablet/capsule opaquants (examples include but are not limited to    titanium dioxide);-   tablet polishing agents (examples include but are not limited to    carnuba wax and white wax);-   thickening agents (examples include but are not limited to beeswax,    cetyl alcohol and paraffin);-   tonicity agents (examples include but are not limited to dextrose    and sodium chloride);-   viscosity increasing agents (examples include but are not limited to    alginic acid, bentonite, carbomers, carboxymethylcellulose sodium,    methylcellulose, polyvinyl pyrrolidone, sodium alginate and    tragacanth); and-   wetting agents (examples include but are not limited to    heptadecaethylene oxycetanol, lecithins, sorbitol monooleate,    polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

Pharmaceutical compositions according to the present invention can beillustrated as follows:

Sterile IV Solution: A 5 mg/mL solution of the desired compound of thisinvention can be made using sterile, injectable water, and the pH isadjusted if necessary. The solution is diluted for administration to 1-2mg/mL with sterile 5% dextrose and is administered as an IV infusionover about 60 minutes.

Lyophilized powder for IV administration: A sterile preparation can beprepared with (i) 100-1000 mg of the desired compound of this inventionas a lypholized powder, (ii) 32-327 mg/mL sodium citrate, and (iii)300-3000 mg Dextran 40. The formulation is reconstituted with sterile,injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL,which is further diluted with saline or dextrose 5% to 0.2-0.4 mg/mL,and is administered either IV bolus or by IV infusion over 15-60minutes.

Intramuscular suspension: The following solution or suspension can beprepared, for intramuscular injection:

-   50 mg/mL of the desired, water-insoluble compound of this invention-   5 mg/mL sodium carboxymethylcellulose-   4 mg/mL TWEEN 80-   9 mg/mL sodium chloride-   9 mg/mL benzyl alcohol

Hard Shell Capsules: A large number of unit capsules are prepared byfilling standard two-piece hard galantine capsules each with 100 mg ofpowdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6mg of magnesium stearate.

Soft Gelatin Capsules: A mixture of active ingredient in a digestibleoil such as soybean oil, cottonseed oil or olive oil is prepared andinjected by means of a positive displacement pump into molten gelatin toform soft gelatin capsules containing 100 mg of the active ingredient.The capsules are washed and dried. The active ingredient can bedissolved in a mixture of polyethylene glycol, glycerin and sorbitol toprepare a water miscible medicine mix.

Tablets: A large number of tablets are prepared by conventionalprocedures so that the dosage unit is 100 mg of active ingredient, 0.2mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg ofmicrocrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose.Appropriate aqueous and non-aqueous coatings may be applied to increasepalatability, improve elegance and stability or delay absorption.

Immediate Release Tablets/Capsules: These are solid oral dosage formsmade by conventional and novel processes. These units are taken orallywithout water for immediate dissolution and delivery of the medication.The active ingredient is mixed in a liquid containing ingredient such assugar, gelatin, pectin and sweeteners. These liquids are solidified intosolid tablets or caplets by freeze drying and solid state extractiontechniques. The drug compounds may be compressed with viscoelastic andthermoelastic sugars and polymers or effervescent components to produceporous matrices intended for immediate release, without the need ofwater.

Method of Treating Hyper-Proliferative Disorders

The present invention relates to a method for using the compounds of thepresent invention and compositions thereof, to treat mammalianhyper-proliferative disorders. Compounds can be utilized to inhibit,block, reduce, decrease, etc., cell proliferation and/or cell division,and/or produce apoptosis. This method comprises administering to amammal in need thereof, including a human, an amount of a compound ofthis invention, or a pharmaceutically acceptable salt, isomer,polymorph, metabolite, hydrate, solvate or ester thereof; etc. which iseffective to treat the disorder. Hyper-proliferative disorders includebut are not limited, e.g., psoriasis, keloids, and other hyperplasiasaffecting the skin, benign prostate hyperplasia (BPH), solid tumors,such as cancers of the breast, respiratory tract, brain, reproductiveorgans, digestive tract, urinary tract, eye, liver, skin, head and neck,thyroid, parathyroid and their distant metastases. Those disorders alsoinclude lymphomas, sarcomas, and leukemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem andhypophtalmic glioma, cerebellar and cerebral astrocytoma,medulloblastoma, ependymoma, as well as neuroectodermal and pinealtumor.

Tumors of the male reproductive organs include, but are not limited toprostate and testicular cancer. Tumors of the female reproductive organsinclude, but are not limited to endometrial, cervical, ovarian, vaginal,and vulvar cancer, as well as sarcoma of the uterus.

Tumors of the digestive tract include, but are not limited to anal,colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal,small-intestine, and salivary gland cancers.

Tumors of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, urethral and human papillary renalcancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellularcarcinoma (liver cell carcinomas with or without fibrolamellar variant),cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixedhepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to laryngeal,hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oralcavity cancer and squamous cell. Lymphomas include, but are not limitedto AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-celllymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of thecentral nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

These disorders have been well characterized in humans, but also existwith a similar etiology in other mammals, and can be treated byadministering pharmaceutical compositions of the present invention.

The term “treating” or “treatment” as stated throughout this document isused conventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving thecondition of, etc., of a disease or disorder, such as a carcinoma.

Methods of Treating Kinase Disorders

The present invention also provides methods for the treatment ofdisorders associated with aberrant kinase activity (such as tyrosinekinase activity), including, FGFR1, FGFR2, FGFR3, FGFR4, VEGFR1, VEGFR2,VEGFR3, Tie2, PDGFR, Aurora A, Aurora B, EphB4, EphA2, p70S6K, RSK,TrkA, Trk B, RET, Src, c-Yes and Fyn.

Effective amounts of compounds of the present invention can be used totreat such disorders, including those diseases (e.g., cancer) mentionedin the Background section above. Nonetheless, such cancers and otherdiseases can be treated with compounds of the present invention,regardless of the mechanism of action and/or the relationship betweenthe kinase and the disorder.

The phrase “aberrant kinase activity” or “aberrant tyrosine kinaseactivity,” includes any abnormal expression or activity of the geneencoding the kinase or of the polypeptide it encodes. Examples of suchaberrant activity, include, but are not limited to, over-expression ofthe gene or polypeptide; gene amplification; mutations which produceconstitutively-active or hyperactive kinase activity; gene mutations,deletions, substitutions, additions, etc.

The present invention also provides for methods of inhibiting a kinaseactivity, especially of FGFR1, FGFR2, FGFR3, FGFR4, VEGFR1, VEGFR2,VEGFR3, Tie2, PDGFR, Aurora A, Aurora B, EphB4, EphA2, p70S6K, RSK,TrkA, Trk B, RET, Src, c-Yes and Fyn comprising administering aneffective amount of a compound of the present invention, includingsalts, polymorphs, metabolites, hyrates, solvates, prodrugs (e.g.:esters) thereof, and diastereoisomeric forms thereof. Kinase activitycan be inhibited in cells (e.g., in vitro), or in the cells of amammalian subject, especially a human patient in need of treatment.

Methods of Treating Angiogenic Disorders

The present invention also provides methods of treating disorders anddiseases associated with excessive and/or abnormal angiogenesis.

Inappropriate and ectopic expression of angiogenesis can be deleteriousto an organism. A number of pathological conditions are associated withthe growth of extraneous blood vessels. These include, e.g., diabeticretinopathy, ischemic retinal-vein occlusion, and retinopathy ofprematurity (Aiello et al. New Engl. J. Med. 1994, 331, 1480; Peer etal. Lab. Invest. 1995, 72, 638), age-related macular degeneration (AMD;see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855),neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma,inflammation, rheumatoid arthritis (RA), restenosis, in-stentrestenosis, vascular graft restenosis, etc. In addition, the increasedblood supply associated with cancerous and neoplastic tissue, encouragesgrowth, leading to rapid tumor enlargement and metastasis. Moreover, thegrowth of new blood and lymph vessels in a tumor provides an escaperoute for renegade cells, encouraging metastasis and the consequencespread of the cancer. Thus, compounds of the present invention can beutilized to treat and/or prevent any of the aforementioned angiogenesisdisorders, e.g., by inhibiting and/or reducing blood vessel formation;by inhibiting, blocking, reducing, decreasing, etc. endothelial cellproliferation or other types involved in angiogenesis, as well ascausing cell death or apoptosis of such cell types.

Dose and Administration

Based upon standard laboratory techniques known to evaluate compoundsuseful for the treatment of hyper-proliferative disorders and angiogenicdisorders, by standard toxicity tests and by standard pharmacologicalassays for the determination of treatment of the conditions identifiedabove in mammals, and by comparison of these results with the results ofknown medicaments that are used to treat these conditions, the effectivedosage of the compounds of this invention can readily be determined fortreatment of each desired indication. The amount of the activeingredient to be administered in the treatment of one of theseconditions can vary widely according to such considerations as theparticular compound and dosage unit employed, the mode ofadministration, the period of treatment, the age and sex of the patienttreated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered willgenerally range from about 0.001 mg/kg to about 200 mg/kg body weightper day, and preferably from about 0.01 mg/kg to about 20 mg/kg bodyweight per day. Clinically useful dosing schedules will range from oneto three times a day dosing to once every four weeks dosing. Inaddition, “drug holidays” in which a patient is not dosed with a drugfor a certain period of time, may be beneficial to the overall balancebetween pharmacological effect and tolerability. A unit dosage maycontain from about 0.5 mg to about 1500 mg of active ingredient, and canbe administered one or more times per day or less than once a day. Theaverage daily dosage for administration by injection, includingintravenous, intramuscular, subcutaneous and parenteral injections, anduse of infusion techniques will preferably be from 0.01 to 200 mg/kg oftotal body weight. The average daily rectal dosage regimen willpreferably be from 0.01 to 200 mg/kg of total body weight. The averagedaily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kgof total body weight. The average daily topical dosage regimen willpreferably be from 0.1 to 200 mg administered between one to four timesdaily. The transdermal concentration will preferably be that required tomaintain a daily dose of from 0.01 to 200 mg/kg. The average dailyinhalation dosage regimen will preferably be from 0.01 to 100 mg/kg oftotal body weight.

Of course the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific compound employed, the age and general condition of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a compound of the present inventionor a pharmaceutically acceptable salt or ester or composition thereofcan be ascertained by those skilled in the art using conventionaltreatment tests.

Combination Therapies

The compounds of this invention can be administered as the solepharmaceutical agent or in combination with one or more otherpharmaceutical agents where the combination causes no unacceptableadverse effects. For example, the compounds of this invention can becombined with known anti-hyper-proliferative or other indication agents,and the like, as well as with admixtures and combinations thereof.

The additional pharmaceutical agent can be aldesleukin, alendronic acid,alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine,aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole,anzmet, aranesp, arglabin, arsenic trioxide, aromasin, 5-azacytidine,azathioprine, BCG or tice BCG, bestatin, betamethasone acetate,betamethasone sodium phosphate, bexarotene, bleomycin sulfate,broxuridine, bortezomib, busulfan, calcitonin, campath, capecitabine,carboplatin, casodex, cefesone, celmoleukin, cerubidine, chlorambucil,cisplatin, cladribine, cladribine, clodronic acid, cyclophosphamide,cytarabine, dacarbazine, dactinomycin, DaunoXome, decadron, decadronphosphate, delestrogen, denileukin diftitox, depo-medrol, deslorelin,dexrazoxane, diethylstilbestrol, diflucan, docetaxel, doxifluridine,doxorubicin, dronabinol, DW-166HC, eligard, elitek, ellence, emend,epirubicin, epoetin alfa, epogen, eptaplatin, ergamisol, estrace,estradiol, estramustine phosphate sodium, ethinyl estradiol, ethyol,etidronic acid, etopophos, etoposide, fadrozole, farston, filgrastim,finasteride, fligrastim, floxuridine, fluconazole, fludarabine,5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU),fluoxymesterone, flutamide, formestane, fosteabine, fotemustine,fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel,goserelin, granisetron HCl, histrelin, hycamtin, hydrocortone,eyrthro-hydroxynonyladenine, hydroxyurea, ibritumomab tiuxetan,idarubicin, ifosfamide, interferon alpha, interferon-alpha 2, interferonalfa-2A, interferon alfa-2B, interferon alfa-n1, interferon alfa-n3,interferon beta, interferon gamma-1a, interleukin-2, intron A, iressa,irinotecan, kytril, lentinan sulphate, letrozole, leucovorin,leuprolide, leuprolide acetate, levamisole, levofolinic acid calciumsalt, levothroid, levoxyl, lomustine, lonidamine, marinol,mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrolacetate, melphalan, menest, 6-mercaptopurine, Mesna, methotrexate,metvix, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone,Modrenal, Myocet, nedaplatin, neulasta, neumega, neupogen, nilutamide,nolvadex, NSC-631570, OCT-43, octreotide, ondansetron HCl, orapred,oxaliplatin, paclitaxel, pediapred, pegaspargase, Pegasys, pentostatin,picibanil, pilocarpine HCl, pirarubicin, plicamycin, porfimer sodium,prednimustine, prednisolone, prednisone, premarin, procarbazine,procrit, raltitrexed, rebif, rhenium-186 etidronate, rituximab,roferon-A, romurtide, salagen, sandostatin, sargramostim, semustine,sizofiran, sobuzoxane, solu-medrol, sparfosic acid, stem-cell therapy,streptozocin, strontium-89 chloride, synthroid, tamoxifen, tamsulosin,tasonermin, tastolactone, taxotere, teceleukin, temozolomide,teniposide, testosterone propionate, testred, thioguanine, thiotepa,thyrotropin, tiludronic acid, topotecan, toremifene, tositumomab,trastuzumab, treosulfan, tretinoin, trexall, trimethylmelamine,trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine,valrubicin, vesnarinone, vinblastine, vincristine, vindesine,vinorelbine, virulizin, zinecard, zinostatin stimalamer, zofran,ABI-007, acolbifene, actimmune, affinitak, aminopterin, arzoxifene,asoprisnil, atamestane, atrasentan, BAY 43-9006 (sorafenib), avastin,CCI-779, CDC-501, celebrex, cetuximab, crisnatol, cyproterone acetate,decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, edotecarin,eflornithine, exatecan, fenretinide, histamine dihydrochloride,histrelin hydrogel implant, holmium-166 DOTMP, ibandronic acid,interferon gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanin,L-651582, lanreotide, lasofoxifene, libra, lonafarnib, miproxifene,minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin,neovastat, nolatrexed, oblimersen, onco-TCS, osidem, paclitaxelpolyglutamate, pamidronate disodium, PN-401, QS-21, quazepam, R-1549,raloxifene, ranpirnase, 13-cis-retinoic acid, satraplatin, seocalcitol,T-138067, tarceva, taxoprexin, thymosin alpha 1, tiazofurine,tipifarnib, tirapazamine, TLK-286, toremifene, TransMID-107R, valspodar,vapreotide, vatalanib, verteporfin, vinflunine, Z-100, zoledronic acidor combinations thereof.

Optional anti-hyper-proliferative agents which can be added to thecomposition include but are not limited to compounds listed on thecancer chemotherapy drug regimens in the 11^(th) Edition of the MerckIndex, (1996), which is hereby incorporated by reference, such asasparaginase, bleomycin, carboplatin, carmustine, chlorambucil,cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine,dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin,etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide,irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine,mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone,prednisone, procarbazine, raloxifen, streptozocin, tamoxifen,thioguanine, topotecan, vinblastine, vincristine, and vindesine.

Other anti-hyper-proliferative agents suitable for use with thecomposition of the invention include but are not limited to thosecompounds acknowledged to be used in the treatment of neoplasticdiseases in Goodman and Gilman's The Pharmacological Basis ofTherapeutics (Ninth Edition), editor Molinoff et al., publ. byMcGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated byreference, such as aminoglutethimide, L-asparaginase, azathioprine,5-azacytidine cladribine, busulfan, diethylstilbestrol,2′,2′-difluorodeoxycytidine, docetaxel, erythrohydroxynonyl adenine,ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridinemonophosphate, fludarabine phosphate, fluoxymesterone, flutamide,hydroxyprogesterone caproate, idarubicin, interferon,medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane,paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA),plicamycin, semustine, teniposide, testosterone propionate, thiotepa,trimethylmelamine, uridine, and vinorelbine.

Other anti-hyper-proliferative agents suitable for use with thecomposition of the invention include but are not limited to otheranti-cancer agents such as epothilone and its derivatives, irinotecan,raloxifen and topotecan.

Generally, the use of cytotoxic and/or cytostatic agents in combinationwith a compound or composition of the present invention will serve to:

-   (1) yield better efficacy in reducing the growth of a tumor or even    eliminate the tumor as compared to administration of either agent    alone,-   (2) provide for the administration of lesser amounts of the    administered chemo-therapeutic agents,-   (3) provide for a chemotherapeutic treatment that is well tolerated    in the patient with fewer deleterious pharmacological complications    than observed with single agent chemotherapies and certain other    combined therapies,-   (4) provide for treating a broader spectrum of different cancer    types in mammals, especially humans,-   (5) provide for a higher response rate among treated patients,-   (6) provide for a longer survival time among treated patients    compared to standard chemotherapy treatments,-   (7) provide a longer time for tumor progression, and/or-   (8) yield efficacy and tolerability results at least as good as    those of the agents used alone, compared to known instances where    other cancer agent combinations produce antagonistic effects.

EXPERIMENTAL

Abbreviations and Acronyms

A comprehensive list of the abbreviations used by organic chemists ofordinary skill in the art appears in The ACS Style Guide (third edition)or the Guidelines for Authors for the Journal of Organic Chemistry. Theabbreviations contained in said lists, and all abbreviations utilized byorganic chemists of ordinary skill in the art are hereby incorporated byreference. For purposes of this invention, the chemical elements areidentified in accordance with the Periodic Table of the Elements, CASversion, Handbook of Chemistry and Physics, 67th Ed., 1986-87.

More specifically, when the following abbreviations are used throughoutthis disclosure, they have the following meanings:

Abbreviations and Acronyms ¹H-NMR proton nuclear magnetic resonancespectroscopy ³¹P-NMR phophorus-31 nuclear magnetic resonancespectroscopy AcOH acetic acid (Ac)₂O acetic anhydride abs absolute aqaqueous ap approximate atm atmosphere br broad BOPbenzotriazole-1-yloxy-tris(dimethylarnino)phosphoniumhexafluorophosphate Bu butyl ACN acetonitrile Ac₂O acetic anhydride AcOHacetic acid Celite ® brand of diatomaceous earth from Celite Corp. CD₃CNacetonitrile-d₃ CD₃OD methanol-d₄ d doublet DCE dichloroethane DCMdichloromethane dd double doublet DIBAL diisobutylaluminum hydride DMFN,N-dimethylformamide DMSO dimethylsulfoxide DMSO-d₆dimethyldsulfoxide-d₆ equiv equivalent(s) ES-MS electrospray massspectrometry Et₃N triethylamine Et₂O diethyl ether EtOAc ethyl acetateEtOH ethanol FBS fetal bovine serum g gram(s) h hour(s) HPLC highperformance liquid chromatography Hz hertz J NMR coupling constant Lliter(s) LCMS liquid chromatography-mass spectrometry LHMDS lithiumhexamethyldisilazide L-Selectride lithium tri-sec-butylborohydride Mmolar Me methyl MeOH methanol mg milligram(s) MHz megahertz minminute(s) mL milliliter mmol millimole MPLC medium pressure liquidchromatography MS mass spectrometry Ms methanesulfonyl N normal nMnanomolar Pr propyl py-BOPbenzotriazol-1-yl-oxytripyrrolidineophosponium hexafluorophosphate qquartet Ra-Ni Raney-Nickel R_(f) TLC retention factor Rochelle'spotassium sodium tartrate salt RP Reverse phase RPMI Roswell ParkMemorial Institute RT retention time rt room temperature s singlet ttriplet TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuranTLC thin layer chromatography TosMIC Tosylmethyl isocyanide TPPtriphenylphosphine Ts p-toluenesulfonyl v/v volume-to-volume proportionv/v/v volume-to-volume-to-volume proportion μL microliter μm micrometer

The percentage yields reported in the following examples are based onthe starting component that was used in the lowest molar amount. Air andmoisture sensitive liquids and solutions were transferred via syringe orcannula, and introduced into reaction vessels through rubber septa.Commercial grade reagents and solvents were used without furtherpurification. The term “concentrated under reduced pressure” refers touse of a Buchi rotary evaporator at approximately 15 mm of Hg. Alltemperatures are reported uncorrected in degrees Celsius (° C.). Thinlayer chromatography (TLC) was performed on pre-coated glass-backedsilica gel 60 A F-254 250 μm plates.

The structures of compounds of this invention were confirmed using oneor more of the following procedures.

NMR

NMR spectra were acquired for each compound and were consistent with thestructures shown.

Routine one-dimensional NMR spectroscopy was performed on either 300 or400 MHz Varian® Mercury-plus spectrometers. The samples were dissolvedin deuterated solvents. Chemical shifts were recorded on the ppm scaleand were referenced to the appropriate solvent signals, such as 2.49 ppmfor DMSO-d6, 1.93 ppm for CD3CN, 3.30 ppm for CD3OD, 5.32 ppm for CD2Cl2and 7.26 ppm for CDCl3 for 1H spectra.

GC/MS

Electron impact mass spectra (EI-MS) were obtained with a HewlettPackard 5973 mass spectrometer equipped Hewlett Packard 6890 GasChromatograph with a J & W HP-5 column (0.25 uM coating; 30 m×0.32 mm).The ion source was maintained at 250° C. and spectra were scanned from50-550 amu at 0.34 sec per scan.

LC/MS

Unless otherwise noted, all retention times are obtained from the LC/MSand correspond to the molecular ion. High pressure liquidchromatography-electrospray mass spectra (LC/MS) were obtained using oneof the following:

Method A (LCQ)

Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variablewavelength detector set at 254 nm, a Waters Sunfire C18 column (2.1×30mm, 3.5 □m), a Gilson autosampler and a Finnigan LCQ ion trap massspectrometer with electrospray ionization. Spectra were scanned from120-1200 amu using a variable ion time according to the number of ionsin the source. The eluents were A: 2% acetonitrile in water with 0.02%TFA, and B: 2% water in acetonirile with 0.018% TFA. Gradient elutionfrom 10% B to 95% B over 3.5 minutes at a flow rate of 1.0 mL/min wasused with an initial hold of 0.5 minutes and a final hold at 95% B of0.5 minutes. Total run time was 6.5 minutes.

Method B (LCQ5)

Agilent 1100 HPLC system. The Agilent 1100 HPLC system was equipped withan Agilent 1100 autosampler, quaternary pump, a variable wavelengthdetector set at 254 nm. The HPLC column used was a Waters Sunfire C-18column (2.1×30 mm, 3.5 □m). The HPLC eluent was directly coupled withoutsplitting to a Finnigan LCQ DECA ion trap mass spectrometer withelectrospray ionization. Spectra were scanned from 140-1200 amu using avariable ion time according to the number of ions in the source usingpositive ion mode. The eluents were A: 2% acetonitrile in water with0.02% TFA, and B: 2% water in acetonirile with 0.02% TFA. Gradientelution from 10% B to 90% B over 3.0 minutes at a flow rate of 1.0mL/min was used with an initial hold of 1.0 minutes and a final hold at95% B of 1.0 minutes. Total run time was 7.0 minutes.

Method C (LTQ)

Agilent 1100 HPLC system. The Agilent 1100 HPLC system was equipped withan Agilent 1100 autosampler, quaternary pump, and a diode array. TheHPLC column used was a Waters Sunfire C18 column (2.1×30 mm, 3.5 □m).The HPLC eluent was directly coupled with a 1:4 split to a Finnigan LTQion trap mass spectrometer with electrospray ionization. Spectra werescanned from 50-800 amu using a variable ion time according to thenumber of ions in the source using positive or negative ion mode. Theeluents were A: water with 0.1 formic acid, and B: acetonitrile with0.1% formic acid. Gradient elution from 10% B to 90% B over 3.0 minutesat a flowrate of 1.0 mL/min was used with an initial hold of 2.0 minutesand a final hold at 95% B of 1.0 minutes. Total run time was 8.0minutes.

Method D

Gilson HPLC system equipped with a variable wavelength detector set at254 nm, a YMC pro C-18 column (2×23 mm, 120 A), and a Finnigan LCQ iontrap mass spectrometer with electrospray ionization. Spectra werescanned from 120-1200 amu using a variable ion time according to thenumber of ions in the source. The eluants were A: 2% acetonitrile inwater with 0.02% TFA and B: 2% water in acetonitrile with 0.018% TFA.Gradient elution from 10% B to 95% over 3.5 minutes at a flow rate of1.0 mL/min was used with an initial hold of 0.5 minutes and a final holdat 95% B of 0.5 minutes. Total run time was 6.5 minutes.

Method E

Agilent 1100 HPLC system. The Agilent 1100 HPLC system was equipped withan Agilent 1100 autosampler, quaternary pump, and a diode array. TheHPLC column used was a Waters Sunfire (2.1×30 mm, 3.5 □m). The HPLCeluent was directly coupled with a 1:4 split to a Finnigan LTQ ion trapmass spectrometer with electrospray ionization. Spectra were scannedfrom 50-1000 amu using a variable ion time according to the number ofions in the source in either positive or negative ion mode. The eluentswere A: water with 0.1 formic acid, and B: acetonitrile with 0.1% formicacid. Gradient elution from 10% B to 90% B over 3.0 minutes at a flowrate of 1.0 mL/min was used with an initial hold of 2.0 minutes and afinal hold at 95% B of 1.0 minutes. Total run time was 8.0 minutes.

Preparative HPLC:

Preparative HPLC was carried out in reversed phase mode, typically usinga Gilson HPLC system equipped with two Gilson 322 pumps, a Gilson 215Autosampler, a Gilson diode array detector, and a C-18 column (e.g. YMCPro 20×150 mm, 120 A). Gradient elution was used with solvent A as waterwith 0.1% TFA, and solvent B as acetonitrile with 0.1% TFA. Followinginjection onto the column as a solution, the compound was typicallyeluted with a mixed solvent gradient, such as 10-90% Solvent B inSolvent A over 15 minutes with flow rate of 25 mL/min. The fraction(s)containing the desired product were collected by UV monitoring at 254 or220 nm.

Preparative MPLC:

Preparative medium pressure liquid chromatography (MPLC) was carried outby standard silica gel “flash chromatography” techniques (e.g., Still,W. C. et al. J. Org. Chem. 1978, 43, 2923-5), or by using silica gelcartridges and devices such as the Biotage Flash systems. A variety ofeluting solvents were used, as described in the experimental protocols.

General Preparative Methods

The particular process to be utilized in the preparation of thecompounds used in this embodiment of the invention depends upon thespecific compound desired. Such factors as the selection of the specificsubstituents play a role in the path to be followed in the preparationof the specific compounds of this invention. Those factors are readilyrecognized by one of ordinary skill in the art.

The compounds of the invention may be prepared by use of known chemicalreactions and procedures. Nevertheless, the following generalpreparative methods are presented to aid the reader in synthesizing thecompounds of the present invention, with more detailed particularexamples being presented below in the experimental section describingthe working examples.

The compounds of the invention can be made according to conventionalchemical methods, and/or as disclosed below, from starting materialswhich are either commercially available or producible according toroutine, conventional chemical methods. General methods for thepreparation of the compounds are given below, and the preparation ofrepresentative compounds is specifically illustrated in examples.

Synthetic transformations that may be employed in the synthesis ofcompounds of this invention and in the synthesis of intermediatesinvolved in the synthesis of compounds of this invention are known by oraccessible to one skilled in the art. Collections of synthetictransformations may be found in compilations, such as:

-   J. March. Advanced Organic Chemistry, 4th ed.; John Wiley: New York    (1992)-   R. C. Larock. Comprehensive Organic Transformations, 2nd ed.;    Wiley-VCH: New York (1999)-   F. A. Carey; R. J. Sundberg. Advanced Organic Chemistry, 2nd ed.;    Plenum Press: New York (1984)-   T. W. Greene; P. G. M. Wuts. Protective Groups in Organic Synthesis,    3rd ed.; John Wiley: New York (1999)-   L. S. Hegedus. Transition Metals in the Synthesis of Complex Organic    Molecules, 2nd ed.; University Science Books: Mill Valley, Calif.    (1994)-   L. A. Paquette, Ed. The Encyclopedia of Reagents for Organic    Synthesis; John Wiley: New York (1994)-   A. R. Katritzky; O. Meth-Cohn; C. W. Rees, Eds. Comprehensive    Organic Functional Group Transformations; Pergamon Press: Oxford, UK    (1995)-   G. Wilkinson; F. G A. Stone; E. W. Abel, Eds. Comprehensive    Organometallic Chemistry; Pergamon Press: Oxford, UK (1982)-   B. M. Trost; I. Fleming. Comprehensive Organic Synthesis; Pergamon    Press: Oxford, UK (1991)-   A. R. Katritzky; C. W. Rees Eds. Comprehensive Heterocylic    Chemistry; Pergamon Press: Oxford, UK (1984)-   A. R. Katritzky; C. W. Rees; E. F. V. Scriven, Eds. Comprehensive    Heterocylic Chemistry II; Pergamon Press: Oxford, UK (1996)-   C. Hansch; P. G. Sammes; J. B. Taylor, Eds. Comprehensive Medicinal    Chemistry: Pergamon Press: Oxford, UK (1990).

In addition, recurring reviews of synthetic methodology and relatedtopics include Organic Reactions; John Wiley: New York; OrganicSyntheses; John Wiley: New York; Reagents for Organic Synthesis: JohnWiley: New York; The Total Synthesis of Natural Products; John Wiley NewYork; The Organic Chemistry of Drug Synthesis; John Wiley: New York;Annual Reports in Organic Synthesis; Academic Press: San Diego Calif.;and Methoden der Organischen Chemie (Houben-Weyl); Thieme: Stuttgart,Germany. Furthermore, databases of synthetic transformations includeChemical Abstracts, which may be searched using either CAS OnLine orSciFinder, Handbuch der Organischen Chemie (Beilstein), which may besearched using SpotFire, and REACCS.

Methods for preparing pyrrolotriazines are also disclosed in publishedU.S. application Ser. No. 10/289,010 (Publication No. US 2003-0186982A1), U.S. Pat. No. 6,670,357 (U.S. application Ser. No. 10/036,293), aswell as WO 2003/042172, WO 2004/009542, WO2004/009601, WO 2004/009784,WO 2004/013145 and WO 2005/121147 all of which are hereby incorporatedby reference in their entirety.

General Methods of Preparation of Invention Compounds

It is also to be understood that starting materials are commerciallyavailable or readily prepared by standard methods well known in the art.Such methods include, but are not limited to the transformations listedherein.

If not mentioned otherwise, the reactions are usually carried out ininert organic solvents which do not change under the reactionconditions. These include ethers, such as diethyl ether, 1,4-dioxane ortetrahydrofuran, halogenated hydrocarbons, such as dichloromethane,trichloromethane, carbon tetrachloride, 1,2-dichloroethane,trichloroethane or tetrachloroethane, hydrocarbons, such as benzene,toluene, xylene, hexane, cyclohexane or mineral oil fractions, alcohols,such as methanol, ethanol or iso-propanol, nitromethane,dimethylformamide or acetonitrile. It is also possible to use mixturesof the solvents.

The reactions are generally carried out in a temperature range of from0° C. to 150° C., preferably from 0° C. to 70° C. The reactions can becarried out under atmospheric, elevated or under reduced pressure (forexample from 0.5 to 5 bar). In general, they are carried out underatmospheric pressure of air or inert gas, typically nitrogen.

Compounds of the present invention of formula I can be prepared bystraightforward means as described in the reaction schemes below or bymeans well known to those skilled in the art. In these reaction schemes,unless otherwise specifically defined, the meanings of R¹, R², R³ and R⁴are identical to those described above.

Reaction Scheme 1 illustrates a general method of preparing compounds offormula I from the corresponding anilino compounds of formula 1-1 bymethods of urea formation well known in the art. Thus, reaction ofanilines of formula-1 with either an isocyanate of formula 1-2 orpreferably a carbamate of formula 1-3, generally in an inert solvent,provides compounds of formula I-1 directly.

Reaction Scheme 2 outlines an alternate method for preparing compoundsof formula I, starting from bromides of formula 2-1, where PG is anoptional protecting group known in the art (or alternatively NHPG=NO₂).Thus, Suzuki reaction of 2-1 with boronates of formula 2-3 underconditions well known in the art provides compounds of formula I.Alternatively, Suzuki reactions of boronatse of formula 2-3 underconditions well known in the art provides anilino-compounds of formula1-1. Such compounds can be converted to the ureas of Formula I byreaction with isocyanates of formula 1-2 or carbamates of formula 1-3,as described in Scheme 1. If necessary, the protecting group (PG) can beremoved first by methods well known in the art (e.g. acid catalyzedremoval of BOC carbamates).

Reaction Schemes 3 outlines the preparation of intermediates of generalformula 3-8, but where R⁴ has been replaced by H and R³ is described asa carboxylic acid derivative (e.g an ester). Thus, beginning with4-nitrocinnamate compounds of formula 5-5, treatment with isocyanidereagents of formula 3-1 in the presence of a strong base such as lithiumhexamethyldisilazide or the like in an aprotic solvent such as THF orthe like provides pyrroles of formula 3-2. Formylation of 3-2 underVilsmeier conditions well known in the art (e.g., DMF, POCl₃) gives2-formylpyrrole compounds of formula 3-3. Compounds of formula 3-3 areconverted to nitriles of Formula 3-4 by reaction with hydroxylaminehydrochloride in a solvent such as pyridine to form an intermediateoxime, which is dehydrated in situ to provide the nitrile, using areagent such as acetic anhydride or the like. Compounds of formula 3-4are N-aminated using a strong base such as NaH or the like and anaminating reagent such as (Ph)₂P(O)—O—NH₂ (compound 3-5) or the like, toprovide N-amino nitriles of formula 3-6. Reaction of 3-6 with formamideprovides pyrrolotriazine intermediates of formula 3-7. Selectivereduction of the nitro substituent of the phenyl ring can beaccomplished by many methods known to those skilled in the art, (e.g.Raney nickel or tin(II) chloride) providing intermediates of formula3-8.

Schemes 4 outlines the preparation of intermediates of formula 3-7,where R⁴ has been replaced by H and R³ is described as a carboxylic acidderivative (e.g an ester). Thus, treatment of with β-ketoesters offormula 4-1 with N,N-dimethylformamide dimethylacetal or the likeprovides compounds of formula 4-2. Reaction of 4-2 with compounds offormula 4-4 in the presence of an acid such as AcOH followed by an acidsuch as trifluoroacetic or the like provides pyrolles of formula 4-5.Treatment of 4-5 with a reagent such as phosphorous oxychloride providescompounds of formula 4-6. Compounds of formula 4-6 are N-aminated usinga strong base such as NaH or the like and an aminating reagent such as(Ph)₂P(O)—O—NH₂ (compound 3-5) or the like, to provide N-amino nitrilesof formula 4-7. Cyclization of 4-7 can be affected by treatment with aformamiding derivative such as formamidine acetate or the like in asolvent such as EtOH to provide pyrrolotriazine intermediates of formula3-7.

The cinnamates of formula 5-5 are either commercially available or canbe prepared as shown in Reaction Scheme 5. In this sequence, substitutednitrotoluenes of formula 5-1 are oxidized with a reagent such aspotassium permanganate or the like to give the corresponding acids offormula 5-2. This acid can in turn be reduced to alcohols of formula 5-3with a reducing agent such as borane or the like in a suitable solventsuch as THF or the like. Treatment of these compounds with an oxidizingreagent such as the Dess-Martin periodinane provides aldehydes offormula 5-4. Wadsworth-Emmons type reaction of 5-4 using(EtO)₂P(O)CH₂CO₂Et or the like and a strong base such as LiH or the likeprovides cinnamates of formula 5-5.

Reaction Scheme 6 outlines a preparation of intermediate compounds ofgeneral formula 6-7, where E³ is described as a subset of R³, E⁴ isdefined as a subset of R⁴ which also includes H, and G¹ is described asNH₂, NHPG, NO₂ or NH(CO)NHR¹. Thus, treatment of pyrrole 6-1 (where PGis an optional protecting group such as2,2-(trimethylsilyl)ethoxymethyl) with an appropriate electrophile E³(e.g. chlorosulfonyl isocyanate) under conditions well known to thosefamiliar with the art, provides compounds of formula 6-2. Treatment of6-2 with a brominating reagent such as 1,3-dibromo-5,5-dimethylhydantoinor the like, in a solvent, such as DMF or the like, provides dibromidesof formula 6-3. Regioselective metallation of 6-3 with an organometallicreagent such as n-butyllithium or the like in a solvent such as THF orthe like, followed by addition of an appropriate electrophile E⁴ (e.g.substituted alkyl halide or simply a proton) provides substitutedpyrolles of formula 6-4. Compounds of formula 6-4 are N-aminated using astrong base such as NaH or the like and an aminating reagent such as(Ph)₂P(O)—O—NH₂ (compound 3-5) or the like, to provide N-amino nitrilesof formula 6-6 If necessary, the protecting group (PG) can be removedfirst using methods well known to those versed in the art. Treatment of6-6 with a reagent such as formamidine preferably in the presence of abase such as potassium carbonate provides compounds of formula 6-7.

Reaction Scheme 7 outlines a preparation of intermediate compounds ofgeneral formula 7-8. These compounds are described as having the samegeneral structure as compounds 2-1, but here G³ is defined as a subsetof R³ and E⁴ is defined as a subset of R⁴. Treatment of a suitablyprotected (e.g. a protecting group well known to those skilled in theart) hydrazine derivative with a 2,5-dialkoxy tetrahydrofuran derivativein the presence of an acid, such as HCl or the like in a solvent such as1,4-dioxane or the like provides the protected aminopyrrole derivative7-1. Cyanation using chlorosulfonyl isocyanate in a solvent such asacetonitrile or the like provides 2-cyano derivatives of formula 7-2.Treatment of 6-2 with a brominating reagent such as1,3-dibromo-5,5-dimethylhydantoin or the like, in a solvent, such as DMFor the like, provides bromides of formula 7-3, which upon deprotection(using procedures/reagents known in the art) liberate aminopyrroleproducts of formula 7-4. Reaction of 7-4 with a formamidine reagent inthe presence of a base such as potassium phosphate or the like in asolvent such as ethanol or similar provides compounds of structure 7-5.Reaction of 7-5 with organometallic reagents, (e.g. methylzinc chloride)under palladium catalyzed conditions well known to those skilled in theart, provides compounds of formula 7-6. Reaction of 7-6 with anappropriate electrophile E⁴ (e.g. Mannich conditions) provides compoundsof formula 7-7. Bromination of 7-7 with brominating reagent, such as1,3-dibromo-5,5-dimethylhydantoin or another appropriate agent in anappropriate solvent, such as DMF or the like, and provides 7-8. Thefollowing schemes demonstrate the interconversion of compounds offormula 6-7 and 7-8 to yield a variety of functionalities.

Reaction Scheme 8 describes methods in which the R⁴ functionality can beintroduced and modified into a variety of functionalities, where G¹ isdefined as —NH₂, NO₂, NH(CO)NHR¹, or NHPG and G² is defined as in Scheme8 and where Z⁴ is defined as an aryl or heteroaryl group. Beginning withcompounds of formula 8-1, treatment with with an appropriate brominatingreagent, such as 1,3-dibromo-5,5-dimethylhydantoin or the like, in asolvent, such as DMF or the like, provides bromide compounds of formula8-2. Bromides of formula 8-2 can be further functionalized in severalways. First, Suzuki reaction of I-2 with aryl boronic acids underconditions well known in the art provides compounds of formula 8-3.Alternatively, treatment of 8-2 with cyanide salts such as copper(I)cyanide or the like in a solvent such as DMF or the like provides cyanocompounds of formula 8-4. Similarly, metallation of 8-2 by treatmentwith an organometallic such as n-butyllithium or the like, followed bytreatment with an electrophile such as DMF or the like, providesaldehydes of formula 8-5.

Reaction Scheme 9 describes the preparation of ketone compounds offormula 9-2, where G² is defined as above in Scheme 8. Thus, treatmentof compounds of formula 8-5 with an organometallic such as a Grignardreagent or the like, in an appropriate solvent such as THF or the likeprovides alcohols of formula 9-1. Oxidation of these compounds with areagent such as the Dess-Martin periodinane or the like in a solventsuch as THF provides ketones of formula 9-2.

Reaction Scheme 10 outlines some of the ways in which functionality atthe R⁴ position can be introduced and modified. In all cases G² isdefined as above in Scheme 8. Thus, treatment of compounds of formula8-5 with a reducing agent, preferably DIBAL-H, in a solvent such as THFor the like will provide primary alcohols of formula 10-1. Halogenationof 10-1 with a reagent such as thionyl chloride or the like in asuitable solvent such as CH₂Cl₂ provides α-halo compounds of formula10-2 (X═Cl, Br or I). Treatment of 10-2 with alcohols in a suitablesolvent such as DMF or the like, in the presence of a base such asHunigs base or the like and optionally with a catalyst such as potassiumiodide or the like provides ethers of formula 10-3. Alternatively,treatment of 10-2 with an amine, such as a primary or secondary (cyclicor acyclic) amine, in the presence of a suitable base, such as Hunigsbase or the like provides compounds of structure 10-4. Compounds offormula 10-4 can be directly prepared from 8-5 by treatment with anamine, such as a primary or secondary (cyclic or acyclic) amine, underreductive amination conditions well know in the art (sodiumtriacetoxyborohydride, e.g.).

Compounds of formula 10-4 can also be prepared directly from compoundsof formula 10-5 using Mannich conditions, such as by treatment with anamine, such as a primary or secondary (cyclic or acyclic) amine, andformaldehyde in a solvent such as acetic acid or the like.

Reaction Scheme 11 outlines the preparation of compounds of 11-6 whereinR⁴ is described as a heteroatom functionality attached to a 2 carbonlinker and G² is defined as above in Scheme 8. Metallation of compoundsof formula 11-1 with an organometallic reagent such asisospropylmagnesium chloride or the like in the presence of an in situprotecting group such as chlortrimethylsilane or the like followed bytreatment with Weinreb amide 11-2 provides α-haloketones of formula11-3. These compounds can be converted to compounds of formula 11-4 bytreatment with a nucleophile Nu, wherein Nu is defined as an amine, suchas a primary or secondary (cyclic or acyclic) amine, or as an alcohol,in a suitable solvent such as DMF or the like and optionally in thepresence of a catalyst such as potassium iodide and/or a base such aspotassium carbonate or the like. Treatment of 11-4 with a reducing agentsuch as DIBAL-H or the like in a solvent such as THF or the likeprovides compounds of formula 11-5. These compounds can be converted totheir reduced analogs of formula 11-7 by a variety of methods familiarto those skilled in the art. For example, activation of 11-5 with ahalogenating agent such as thionyl chloride or the like in a suitablesolvent such as CH₂Cl₂ or the like provides chlorides of formula 11-6.These compounds can in turn be reduced to compounds of formula 11-7 bytreatment with a suitable reducing agent such as lithiumtriethylborohydride or the like in a suitable solvent such as THF or thelike. Alternatively, compounds of formula 11-5 can be reduced under H₂gas in the presence of a suitable catalyst such as palladium on carbonusing methods well known in the art.

Reaction Scheme 12 outlines the preparation of compounds of formula 12-5wherein R⁴ is described as an heteroatom functionality connected by a 3or 4 carbon linker and G² is defined as above in Scheme 8. Metallationof compounds of formula 8-2 with an organometallic reagent such asisospropylmagnesium chloride or the like in the presence of an in situprotecting group such as chlortrimethylsilane or the like followed bytreatment with an aldehyde of formula 12-1 (where PG=a suitableprotecting group, e.g. a trialkylsilyl group) provides alcohols offormula 12-2. Conversion of 12-2 to compounds of formula 12-3 can beeffected by treatment with triethylsilane in the presence of an acidsuch as trifluoracetic acid or the like or by a two step procedureanalogous to that described previously in Scheme 11. The protectinggroups (PG) used until this point in the sequence can then be removedunder various well-precedented procedures (acid-catalyzed removal oftrialkylsilanes, e.g.), to provide alcohols of formula 12-3. Conversionof 12-3 to compounds of formula 12-4 (where LG is a suitable leavinggroup, e.g. Cl) can be carried out by methods known in the art.Compounds of formula 12-5 are prepared by treatment of 12-4 with variousnucleophiles (e.g., Nu=ROH or HNR′₂) in an appropriate solvent such asDMF or the like and in the presence of a base such as potassiumcarbonate or the like.

Reaction Scheme 13 outlines some methods for the modification of the R³functionality, wherein G² is defined as above in Scheme 8 and G⁴ isdefined as R⁴ or H. Thus, treatment of esters of formula 13-1 with areducing agent such as diisobutylaluminium hydride or the like in asolvent such as THF or the like provides compounds of structure 13-2.Oxidation of these to the aldehyde using Dess-Martin periodinane or thelike in a solvent such as THF or the like provides compounds of formula13-3. Such aldehydes can be converted to cyano compounds of formula 13-4by treatment with hydroxylamine and a reagent such as acetic anhydrideor the like in a solvent such as pyridine or the like. Alternatively,hydrolysis of 13-1 with a base such as sodium hydroxide or the like in asolvent such as ethanol or the like provides acids of formula 13-5.These compounds can be treated with amines, such as a primary orsecondary (cyclic or acyclic) amine, and a peptide coupling reagent suchas py-BOP or the like in a solvent such as DMF to provide amides offormula 13-6.

Reaction Scheme 14 outlines some methods for the modification of the R³functionality, wherein G² is defined as above in Scheme 8 and G⁴ isdefined as R⁴ or H. Thus, compounds of formula 13-2 can be converted tothe corresponding fluorides of formula 14-1 by treatment with a suitablefluorinating reagent such as Deoxo-Fluor™ or the like in a suitablesolvent such as THF or the like. Aldehydes of formula 13-3 can beconverted to difluoride compounds of formula 14-2 using analogousprocedures. Alternatively, treatment of 13-3 with organometallicreagents such as a Grignard reagent or the like in a suitable solventsuch as THF or the like, followed by oxidation of the intermediatealcohol by treatment with a reagent such as the Dess-Martin periodinaneor the like provides ketones of formula 14-3. As in the previousexamples, ketones of formula 14-3 can be converted to fluorides offormula 14-4 via treatment with a suitable fluorinating agent such asDeoxo-Fluor™ or the like.

Reaction Scheme 15 outlines some methods for the modification of the R³functionality, wherein G² is defined as above in Scheme 8 and G⁴ isdefined as R⁴ or H. Treatment of compounds of formula 13-2 with achlorinating agent such as thionyl chloride or the like in a suitablesolvent such as CH₂Cl₂ or the like provides chlorides of formula 15-1.Treatment of 15-1 with an appropriate nucleophile (wherein Nu=R₂NH, ROH,CN⁻, RSH) in the presence of a suitable base such as Hunigs base or thelike in a solvent such as DMF or the like provides compounds of formula15-2. Alternatively, treatment of 15-1 with a reducing agent such alithium triethylborohydride or the like in a suitable solvent such asTHF or the like provides compounds of formula 15-3. Treatment of 15-1with an amine, such as a primary or secondary (cyclic or acyclic) amine,in the presence of a suitable base such as potassium carbonate or thelike or a tertiary amine, such as Hunig's base or the like providescompounds of formula 15-4. Alternatively, amines of formula 15-4 can beprepared from the corresponding aldehydes of formula 13-3 by treatmentwith an amine, such as a primary or secondary (cyclic or acyclic) amine,in the presence of a suitable reducing agent, such as sodiumtriacetoxyborohydride or the like in a suitable solvent such asdichloroethane or the like.

Reaction Scheme 16 outlines some methods for the modification of the R³functionality, wherein G² is defined as above in Scheme 8 and G⁴ isdefined as R⁴ or H. Thus, treatment of 13-3 with (p-tolylsulfonyl)methylisocyanate or the like in the presence of a base such as sodium hydrideor the like in a suitable solvent such as THF or the like providesoxazole compounds of formula 16-1. Treatment of 13-3 with a Grignardreagent or the like in a suitable solvent such as THF or the likeprovides alcohols of formula 16-2. Oxidation of 16-2 with a reagent suchas the Dess-Martin periodinane or the like in a solvent such as THF orthe like provides ketones of formula 16-3. Alternatively, treatment ofamides of formula 16-2 with organometallics such as Grignard reagentsunder similar conditions provides ketones of formula 16-3 directly.

Reaction Scheme 17 outlines methods for the preparation of compounds offormula 17-5, wherein G² is defined as above in Scheme 8. Thus, reactionof compounds of formula 8-2 with an appropriate terminal acetylene offormula 17-1 (wherein X═H or a suitable protecting groups such as atrialkylsilane) in presence of a Pd(II) catalyst, a Cu(I) co-catalystand an amine base such as pyrrolidine or triethylamine or the like, in asolvent such as DMF or the like provides compounds of formula 17-2.Reduction of the triple bond using hydrogen gas in the presence of ametal catalyst such as PtO₂ or the like in a solvent such as acetic acidor the like provides compounds of formula 17-3. Conversion of 17-3 tocompounds of formula 17-4 (where LG is a suitable leaving group) can becarried out by methods known in the art. If necessary, a protectinggroup (PG) can be removed by methods known in the art prior to theconversion to 17-4. Treatment of 17-4 with a primary or secondary amine,or a primary alcohol, in the presence of a suitable base such aspotassium phosphate or the like or a tertiary amine, such as Hunigs Baseor the like provides compounds of formula 17-5.

Reaction Scheme 18 describes the preparation of compounds of formula18-5 (R⁴=unsubstituted piperidine, pyrollidine or azetadine) or 18-6(R⁵=optionally substituted piperidine, pyrollidine or azetadine) whereinG² is defined as above in Scheme 8. Treatment of compound 8-2 with aboronate such as 18-1 under conditions well known in the art providesthe appropriately protected di-dehydrocyclic amines of formula 18-3.Alternatively, such protected amines can be prepared by conversion of8-2 to a Grignard reagent, which can be carried out by reaction with anappropriate Grignard reagent such as isopropylmagnesium chloride, in thepresence of a temporary protecting agent such as trimethylsilyl chloridein a solvent such as THF. This Grignard reagent formed from 8-2 isreacted with a protected piperidone of formula 18-2 to provide, after anelectrophilic workup which eliminates the intermediate hydroxy compound,compounds of formula 18-3. Reduction of the double bond of 18-3 withhydrogen in the presence of a catalyst such as PtO₂ or the like in asolvent such as acetic acid or the like provides cyclic amines offormula 18-4. Deprotection of 18-4 using procedures well known in theart (acid catalyzed deprotection of BOC carbamate, e.g.) providescompounds of formula 18-5. Reaction of compounds of formula 18-4 with anappropriate alkylating agent such as ethylene carbonate in the presenceof a suitable base such as sodium hydroxide provides compounds of theformula 18-6. Compounds of formula 18-6 are also prepared by treatmentof compounds of the formula 18-5 with an aldehyde such as formaldehydeand the like and a reducing agent such as sodium triacetoxyborohydrideor the like in a solvent such as 1,2-dichloroethane or the like.Compounds of formula 18-6 can also be prepared by the reaction of theamines of formula 18-5 with an acylating or sulfonating reagent, such asan acyl anhydride, acyl chloride, sulfonyl chloride or the like, in thepresence of a suitable base such as pyridine, potassium carbonate, atertiary amine or the like, in appropriate solvents such as THF,dichloromethane, or others.

Reaction Scheme 19 describes the preparation of compounds of formula19-2, where Z³ is defined as a subset of R³ containing aryl andheteroaryl functionalities, G² is defined as above in Scheme 8 and G⁴ isdefined as R⁴ or H. Such compounds can be prepared by reaction ofbromides of formula 19-1 with boronates or bonronic acids of formulaH3-B(OR)₂ under Suzuki coupling conditions well known to those versed inthe art. Alternatively, carbonyl compounds of formula 19-3 (R=alkyl orH) can be converted to compounds of formula 19-3 using many routes wellknown to those versed in the art (as shown in Scheme 16, e.g.)

Additionally, sensitive or reactive groups on the compound of thisinvention may need to be protected and deprotected during any of theabove methods. Protecting groups in general may be added and removed byconventional methods well known in the art (see, for example, T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis; Wiley:New York, (1999).

In order that this invention may be better understood, the followingexamples are set forth. These examples are for the purpose ofillustration only, and are not to be construed as limiting the scope ofthe invention in any manner. All publications mentioned herein areincorporated by reference in their entirety.

PREPARATION OF INTERMEDIATES Intermediate A Preparation of ethyl5-cyano-4-(nitrophenyl)-1H-pyrrole-3-carboxylate Preparation 1

Step 1: Preparation of 2-aminomalonamide

A 5 L 4-neck round bottomed flask equipped with an over head stirrer wascharged with commercially available diethyl amino malonate hydrochloride(338 g, 1.596 mol). 7N ammonia in MeOH (2 L) was removed from thefreezer and added cold in one portion. All of the inlet ports werecovered with plastic caps. Over 1 h the reaction mixture turned to aclear yellow color. The flask was vented once with no observableincrease in pressure. The mixture was allowed to stir over night. Aprecipitate had formed, which was isolated by filtration. The powder waswashed with MeOH (500 mL). The light yellow powder was dried over nightin vacuo to provide diamide 2 (170 g, 1.45 mol, 91% yield).

Step 2: Preparation of ethyl3-(dimethylamino)-2-(4-nitrobenzoyl)acrylate

To a solution of Ethyl 4-nitro benzoylacetate (50 g, 210.8 mmol) intoluene (500 mL) was added dimethylformamide dimethyl acetal (42.3 mL,316.2 mmol). The reaction was heated to 80° C. over night. The mixturewas concentrated in vacuo and purified by flash column chromatography(100% Hexane to 10% EtOAc; 90% Hexane until non-polar impurities wereremoved, then 75% EtOAc; 25% Hex to 100% EtOAc for product) to provide ayellow solid in 87% yield (54 g, 184.8 mmol). ¹H-NMR (DMSO-d₆) δ8.26-8.22 (m, 2H), 7.78 (s, 1H), 7.75-7.73 (m, 2H), 3.83 (q, J=7.2 Hz,2H), 3.27 (br s, 3H), 2.69 (br s, 3H), 0.83 (t, J=7.2, 3H); LCMS RT=2.80min; MS {M+H]⁺=292.9.

Step 3: Preparation of title ethyl5-(aminocarbonyl)-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

A 3 L round bottomed flask was charged with ethyl3-(dimethylamino)-2-(4-nitrobenzoyl)acrylate (63.59 g, 217.5 mmol) and2-aminomalonamide (33.12 g, 282.8 mmol) and AcOH (800 mL). The reactionmixture was heated to 80° C. over night. The starting material appearedconsumed by TLC. The AcOH was removed under reduced pressure and TFA(400 mL) was added. The mixture was heated over night at 60° C. Thereaction was cooled to room temperature and the TFA was removed underreduced pressure. The orange oil was washed with saturated aqueousNaHCO₃ (1 L) and solid NaHCO₃ was added until the solution was neutral.The solids were filtered and placed in a 1 L erlenmeyer flask. Thesolids were washed with H₂O (3×1 L) and the water was decanted offthrough the filter. On the last washing the solids were poured onto thefilter and allowed to air dry. The solids were once again removed fromthe filter and washed with Et₂O (4×500 mL). The Et₂O was decanted offthrough the filter and on the final washing the solids were transferredto the filter. An addition portion of Et₂O (200 mL) was used to wash theflask and the filter cake. The product was dried in a vacuum oven at 40°C. over P₂O₅ for 4 h affording ethyl5-(aminocarbonyl)-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate as a tansolid (55.2 g, 182 mmol, 83.7%). ¹H-NMR (DMSO-d₆) δ 12.33 (br s, 1H),8.19-8.15 (m, 2H), 7.57 (d, J=3.6 Hz, 1H), 7.53-7.49 (m, 2H), 7.29 (brs, 1H), 6.41 (br s, 1H), 3.99 (q, J=7.2 Hz, 2H), 1.03 (t, J=7.2 Hz, 3H);LCMS RT=2.79 min; MS {M+H]⁺=304.2.

Step 4: Preparation of Title Compound

A solution of ethyl5-(aminocarbonyl)-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate (55.0 g,181.3 mmol) in POCl₃ (500 mL) was heated to 70° C. for 2 h. TLC analysisindicated that there was complete conversion of starting material.Excess POCl₃ was removed under reduced pressure and the remaining solidswere poured over ice. The pH was adjusted to 8 using 5N NaOH and thesolution was filtered. The product was dried over P₂O₅ under reducedpressure to afford a light brown solid (50.9 g, 178 mmol) in 98% yield.¹H-NMR (DMSO-d₆) δ 12.24 (br s, 1H), 8.28-8.24 (m, 2H), 7.89 (d, J=3.2Hz, 1H), 7.72-7.68 (m, 2H), 4.10 (q, J=7.2 Hz, 2H), 1.14 (t, J=7.2 Hz,3H); LCMS* RT=4.74 min; MS {M−H]⁻=284.0.

Intermediate A Preparation of ethyl5-cyano-4-(nitrophenyl)-1H-pyrrole-3-carboxylate Preparation 2

Step 1: Preparation of ethyl 4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate

To a solution of 1 M lithium hexamethyldisilazide in THF (102.4 mL,102.4 mmol) cooled to −77° C. was added1-[(isocyanomethyl)sulfonyl]-4-methylbenzene (20.0 g, 102.4 mmol) as asolution in THF (100 mL) dropwise over 30 min. The solution was allowedto stir an additional 15 min, and then ethyl(2E)-3-(4-nitrophenyl)acrylate was added dropwise (22.66 g, 102.4 mmol)as a solution in THF (250 mL) over 1 h. The reaction was allowed to warmto rt over 17 h. Aqueous saturated NaHCO₃ (200 mL) was added to thereaction mixture followed by EtOAc (500 mL). The solution wastransferred to a separatory funnel, and the organic layer was collectedand washed with H₂O (100 mL). The aqueous layers were back extractedwith EtOAc (2×150 mL). The combined organic layers dried (MgSO₄),concentrated onto silica gel, and purified by flash columnchromatography (100% CH₂Cl₂ ramping to 95:5 v/v CH₂Cl₂-EtOAc) to afford16.65 g of the above compound as an orange/yellow solid (63.98 mmol,yield 62%). ¹H-NMR (DMSO-d₆) δ 11.78 (br s, 1H), 8.19 to 8.15 (m, 2H),7.76 to 7.73 (m, 2H), 7.57 to 7.56 (m, 1H), 7.22 to 7.21 (m, 1H), 4.18to 4.13 (q, J=7.1 Hz, 2H), 1.21 (t, J=7.1 Hz, 3H); LCMS RT=2.90 min; TLCR_(f)=0.47 (95:5 v/v CH₂Cl₂-EtOAc).

Step 2: Preparation of ethyl5-formyl-4-(nitrophenyl)-1H-pyrrole-3-carboxylate

To a solution of DCE (100 mL) was added DMF (14.96 mL, 194.4 mmol),which was cooled in an ice-salt bath. As POCl₃ (18.12 mL, 194.4 mmol)was slowly added a white precipitate formed. The solution was allowed towarm to rt while vigorously stirring over 30 min. The slurry was againcooled in an ice-salt bath. Ethyl4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate (46.00 g, 176.8 mmol) wasadded as a suspension in DCE (500 mL). The reaction proceeded whilecooling in an ice-salt bath for 1 h, and then was allowed to warm to rtover 17 h. Sodium Acetate (79.75 g, 972.2 mmol) in water (600 mL) wasthen added to the reaction and the solution was heated to 80° C. for 1h. Upon cooling to rt, the solution was transferred to a separatoryfunnel and the organic layer was isolated while the aqueous layer wasback extracted with CH₂Cl₂ (2×150 mL). The combined organic layers weredried (MgSO₄), filtered, and concentrated to dryness. The crude materialwas heated to reflux in toluene (2 L) and to the hot solution was addedhexanes (200 mL). The solution was allowed to slowly cool, and over thefollowing 2 days crystals formed. The crystals were collected, washedwith Et₂O (500 mL), and dried under vacuum to afford 25.53 g of theabove compound as golden needles (88.57 mmol, yield 50%). ¹H-NMR(DMSO-d₆) δ 12.94 (br s, 1H), 9.29 (d, J=0.8 Hz, 1H), 8.25 to 8.22 (m,2H), 7.81 (d, J=2.7 Hz, 1H), 7.74 to 7.71 (m, 2H), 4.12 to 4.06 (q,J=7.1 Hz, 2H), 1.15 to 1.11 (t, J=7.0 Hz, 3H); LCMS RT=2.75 min; TLCR_(f)=0.16 (95:5 v/v CH₂Cl₂-EtOAc).

Step 3: Preparation of ethyl5-cyano-4-(nitrophenyl)-1H-pyrrole-3-carboxylate

To a solution of pyridine (400 mL) was added ethyl5-formyl-4-(nitrophenyl)-1H-pyrrole-3-carboxylate (24.55 g, 85.17 mmol)followed by hydroxylamine hydrochloride (6.51 g, 93.7 mmol). Thesolution was stirred at rt for 2 h, acetic anhydride (17.68 mL, 187.4mmol) was added, and the solution was heated to 80° C. for 17 h. Uponcooling to rt, the reaction mixture was partially concentrated in vacuoand then diluted with EtOAc (300 mL) and H₂O (300 mL). The solution wastransferred to a separatory funnel, and the organic layer was isolatedwhile the aqueous layers were back extracted with EtOAc (2×100 mL). Thecombined organic layers were dried (Na₂SO₄), filtered, and concentratedto dryness. The crude material was then triturated with CH₂Cl₂-Et₂O (1:1v/v, 300 mL). The solid was collected, washed with Et₂O (150 mL), anddried under vacuum to afford 18.94 g of the above compound as a fluffywhite solid (66.40 mmol, yield 78%). ¹H-NMR (DMSO-d₆) δ 13.24 (br s,1H), 8.30 to 8.27 (m, 2H), 7.92 (s, 1H), 7.74 to 7.71 (m, 2H), 4.16 to4.10 (q, J=7.2 Hz, 2H), 1.18 to 1.15 (t, J=7.0 Hz, 3H); LCMS RT=2.97min; TLC R_(f)=0.20 (95:5 v/v CH₂Cl₂-EtOAc).

Intermediate B Preparation of ethyl4-amino-5-(4-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate

Step 1: Preparation of (aminooxy)(diphenyl)phosphine oxide

A 5 L 4-neck round bottom flask (rbf) fitted with an overhead stirrer &a thermocouple was charged with; (1) a solution of NaOH (60.85 g, 1.52mol, 2.4 eq) in 180 mL water, (2) a solution of hydroxylamine-HCl(110.12 g, 1.58 mol, 2.5 eq) in 180 mL water and (3) 180 mL dioxane. Themixture was cooled in an ice/acetone bath to 0° C. 150 g of ice wasadded, followed by a precooled (to about 10° C.) solution ofdiphenylphosphinic chloride (150.0 g, 0.634 mol, 1 eq) in 180 mL dioxane(added all at once). The reaction became very thick with a whiteprecipitate, requiring vigorous stirring. The internal temperature roseto 22° C. After 5 additional minutes stirring (10 minutes maximum), thereaction mixture was diluted with 2.5 L of ice cold water and filteredthru a large fritted funnel (15 cm diameter). The crude material wasleft on the frit to drain for one hour, then transferred back into the 5L rbf. The solid was suspended in 500 mL ice cold 0.25N NaOH solutionand vigorously stirred for five minutes (no more than 10 min), thenfiltered again, washing 2× with ice cold water and left to dry overnighton the fritted filter. The partially dried material was dried for 12 hin a vacuum oven (50° C., 0.1 torr) and then well crushed with a mortar& pestal. An additional 16 h of drying in the vacuum oven afforded 122 g(82%) the above compound as a white powder.

Step 2: Preparation of ethyl1-amino-5-cyano-4-(nitrophenyl)-1H-pyrrole-3-carboxylate

A 3 L 3 neck round bottomed flask was fitted with a reflux condenser andoverhead stirrer and charged with ethyl5-cyano-4-(nitrophenyl)-1H-pyrrole-3-carboxylate (20 g, 70.11 mmol). Toa rapidly stirred solution in DMF (1 L) was added NaH (5×500 mg, 98mmol) portion wise over 20 min. The dark brown solution was allowed tostir for an additional 10 min. The aminating reagent((aminooxy)(diphenyl)phosphine oxide) was added in one portion (21.26 g,91.14 mmol). The reaction mixture immediately solidified. Upon heatingto 60° C. the solids began to disperse. The mixture was eventuallyheated to 80° C. and stirred over night. The reaction mixture was cooledand the solids were filtered off. The filter cake was washed with EtOAc(200 mL) and the filtrate was concentrated in vacuo. The resulting solidwas suspended in Et₂O (300 mL) and filtered to provide a 69% yield ofthe product (14.37 g, 47.86 mmol) as a light tan powder. The product wasused without further purification. ¹H-NMR (DMSO-d₆) δ 8.29-8.24 (m, 2H),7.72 (s, 1H), 7.71-7.68 (m, 2H), 6.71 (s, 2H), 4.09 (q, J=7.2 Hz, 2H),1.12 (t, J=7.2 Hz, 3H); HPLC RT=3.15 min.

Step 3: Preparation of the Title Compound

To a stirred suspension of ethyl1-amino-5-cyano-4-(nitrophenyl)-1H-pyrrole-3-carboxylate (14.37 g, 47.86mmol) in EtOH (800 mL) was added formamidinium acetate (40 g, 383 mmol).The mixture was heated to 80° C. and allowed to stir over the weekend.The reaction was complete by LCMS. The reaction mixture was cooled toroom temperature and then filtered. The reaction vessel was rinsed withH₂O (200 mL). The filter cake was placed in a beaker and washed with H₂O(300 mL). The yellow suspension was filtered again and the filter cakewas washed with H₂O (2×250 mL). The yellow solid was dried over nightunder reduced pressure to provide 83% yield of the title compound (13 g,39.72 mmol). ¹H-NMR (DMSO-d₆) δ 8.27-8.24 (m, 2H), 8.20 (s, 1H), 7.97(s, 1H), 7.66-7.62 (m, 2H), 4.07 (q, J=7.2 Hz, 2H), 1.06 (t, J=7.2 Hz,3H); LCMS RT=2.87 min; MS {M+H]⁺=328.2.

Intermediate C Preparation of ethyl4-amino-5-(3-fluoro-4-nitrophenyl)-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate

Step 1: Preparation of 3-fluoro-4-nitrobenzoyl chloride

To a suspension of 3-fluoro-4-nitrobenzoic acid (30 g, 162.0 mmol) intoluene (500 mL) was added SOCl₂ (35 mL, 486 mmol). The reaction washeated to 110° C. at which point the reaction became homogeneous. Thereaction was stirred at 110° C. for 3 h. The reaction had not gone tocompletion so an additional portion of SOCl₂ (10 mL) was added. Thereaction was stirred for an additional 3 h. A small amount of startingmaterial remained thus a final portion of SOCl₂ (10 mL) was added andthe reaction was heated for 2 h. The resulting green solution was cooledto room temperature and allowed to stand over night. The reactionmixture was filtered and concentrated in vacuo. Toluene (300 mL) wasadded to the resulting oil and removed under reduced pressure (2×). Theproduct was used without further purification.

Step 2: Preparation of ethyl 3-(3-fluoro-4-nitrophenyl)-3-oxopropanoate

A 2 L round bottomed flask was fitted with a mechanical stir motor andnitrogen inlet. To a 10° C. solution of potassium3-ethoxy-3-oxopropanoate (55.15 g, 324 mmol) in THF (500 mL) was addedMgCl₂ (38.56 g, 405 mmol) and Et₃N (45 mL, 324 mmol). The reactionmixture was allowed to warm to 23° C. and stir for 3 h. A solution of3-fluoro-4-nitrobenzoyl chloride (˜162 mmol) in THF (200 mL) was added.The reaction turned yellow instantly and a precipitate formed. THF (200mL) was added to ensure that stirring was not impeded. TLC analysisindicated that the reaction had gone to completion however the reactionwas allowed to stir over night. The reaction was quenched with 2 N HCl(1 L) and extracted with EtOAc (2×500 mL). The organic layer was washedwith saturated NaHCO₃ (500 mL), H₂O (300 mL) and brine (200 mL). Theorganic layer was dried (Na₂SO₄) and concentrated in vacuo. The desiredproduct (37.65 g, 147 mmol) was isolated by flash column chromatographyin 91% yield (1:1 Hex EtOAc) as a yellow solid as a mixture of keto(75%) and enol (25%) tautomers. ¹H-NMR (DMSO-d₆) Keto tautomer δ 8.29(dd, J=8.6, 7.4 Hz, 1H), 8.10 (dd, J=11.6, 2.0 Hz, 1H), 7.94 (m, 1H),4.30 (s, 2H), 4.11 (q, J=7.2 Hz, 2H), 1.17 (t, J=7.2 Hz, 3H); Enoltautomer δ 12.44 (br s, 1H), 8.22 (app t, J=8.2 Hz, 1H), 8.05 (dd,J=12.6, 2.0 Hz, 1H), 7.90 (m, 1H), 6.22 (s, 1H), 4.25 (q, J=7.2 Hz, 2H),1.26 (t, J=7.2 Hz, 3H); LCMS RT=3.14 min; MS {M+H]⁺=311.0.

Step 3: Preparation of ethyl3-(dimethylamino)-2-(3-fluoro-4-nitrobenzoyl)acrylate

To a solution of ethyl 3-fluoro-4-nitro benzoylacetate (39.0 g, 153.0mmol) in toluene (300 mL) was added dimethylformamide dimethylacetal(30.7 mL, 229.5 mmol). The reaction was heated to 80° C. over night. Themixture was concentrated in vacuo and purified by flash columnchromatography (100% Hexane to 10% EtOAc; 90% Hexane until non-polarimpurities were removed, then 75% EtOAc; 25% Hex to 100% EtOAc forproduct) to provide the desired product as a yellow solid in 95% yield(45.21 g, 145.7 mmol). ¹H-NMR (DMSO-d₆) δ 8.17 (dd, J=8.4, 7.8 Hz, 1H),7.82 (s, 1H), 7.62 (dd, J=11.6, 1.6 Hz, 1H), 7.50 (dd, J=8.4, 1.6 Hz,1H), 3.87 (q, J=7.2 Hz, 2H), 3.32 (br s, 3H), 2.71 (br s, 1H), 0.89 (t,J=7.2 Hz, 3H); LCMS* RT=4.52 min; MS {M+H]⁺=311.1.

Step 4: Preparation of Ethyl5-(aminocarbonyl)-4-(3-fluoro-4-nitrophenyl)-1H-pyrrole-3-carboxylate

A 50 mL round bottomed flask was charged with of ethyl3-(dimethylamino)-2-(3-fluoro-4-nitrobenzoyl)acrylate (51.74 g, 166.75mmol) and 2-aminomalonamide (23.4 mg, 200 mmol) and AcOH (1 L). Thereaction mixture was heated to 80° C. over night. The starting materialappeared consumed by TLC. The AcOH was removed under reduced pressureand TFA (300 mL) was added. The mixture was heated over night at 60° C.The reaction was cooled to room temperature and the TEA was removedunder reduced pressure. The orange oil was treated with saturatedaqueous NaHCO₃ (1 L), then solid NaHCO₃ was added until the solution wasneutral. The solids were filtered and placed in a 1 L erlenmeyer flask.The solids were washed with H₂O (3×1 L) and the water was decanted offthrough the filter. On the last washing the solids were poured onto thefilter and allowed to air dry. The solids were once again removed fromthe filter and washed with Et₂O (4×500 mL). The Et₂O was decanted offthrough the filter and on the final washing the solids were transferredto the filter. An addition portion of Et₂O (200 mL) was used to wash theflask and the filter cake. The desired product was dried in a vacuumoven at 40° C. to provide a light tan solid (36.8 g, 114.5 mmol, 69%yield). ¹H-NMR (DMSO-d₆) δ 12.28 (br s, 1H), 8.07 (app t, J=8.4 Hz, 1H),7.57 (s, 1H), 7.46 (dd, J=12.6, 1.6 Hz, 1H), 7.28 (dd, J=8.4, 1.6 Hz,1H), 7.25 (br s, 1H), 6.72 (br s, 1H), 4.01 (q, J=7.2 Hz, 2H), 1.07 (t,J=7.2 Hz, 3H); LCMS* RT=4.45 min; MS {M−H]⁺=320.1.

Step 5: Preparation of Ethyl 5-cyano-4-(3-fluoro-4-nitrophenyl)-1Hpyrrole-3-carboxylate

A solution of intermediate ethyl5-(aminocarbonyl)-4-(3-fluoro-4-nitrophenyl)-1H-pyrrole-3-carboxylate(36.8 mg, 114.5 mmol) in POCl₃ (500 mL) was heated to 70° C. for 2 h.TLC analysis indicated that there was complete conversion of startingmaterial. Excess POCl₃ was removed under reduced pressure and theremaining solids were poured over ice. The pH was adjusted to 8 using 5N NaOH and the solution was filtered. The product was dried over nightunder reduced pressure to afford a light brown solid (33.85 g, 111.6mmol) in 97% yield. ¹H-NMR (DMSO-d₆) δ 13.32 (br s, 1H), 8.21 (app t,J=8.4 Hz, 1H), 7.90 (s, 1H), 7.73 (dd, J=12.4, 2.0 Hz, 1H), 7.51 (m,1H), 4.13 (q, J=7.2 Hz, 2H), 1.15 (t, J=7.2 Hz, 3H); HPLC RT=3.16 min.

Step 6: Preparation of Ethyl1-amino-5-cyano-4-(3-fluoro-4-nitrophenyl)-1H-pyrrole-3-carboxylate

To a solution of ethyl 5-cyano-4-(3-fluoro-4-nitrophenyl)-1Hpyrrole-3-carboxylate (31.9 g, 105.2 mmol) in DMF (1.5 L) was slowlyadded NaH (34.54 g, 136.7 mmol). After the evolution of gas had ceased(aminooxy)(diphenyl)phosphine oxide (34.4 g, 147.3 mmol) was added inone portion. Upon addition of (aminooxy)(diphenyl)phosphine oxide thereaction mixture solidified. The reaction mixture was heated to 80° C.during which time the solids broke up and mixture stirred freely. Thereaction was heated for 3 h, then cooled and the DMF was removed underreduced pressure. The remaining slurry was dissolved in EtOAc (500 mL)and filtered to remove a majority of the phosphinic acid. The filtercake was washed with EtOAc and the organics were concentrated in vacuo.The product was purified by crystallization from hot ACN to provide atan solid (24.0 g, 75.31 mmol) in 71% yield. ¹H-NMR (DMSO-d₆) δ 8.21(app t, J=8.4 Hz, 1H), 7.73 (s, 1H), 7.71 (dd, J=12.4, 2.0 Hz, 1H), 7.48(m, 1H), 6.72 (s, 2H), 4.11 (q, J=7.2 Hz, 2H), 1.14 (t, J=7.2 Hz, 3H).

Step 7: Preparation of the Title Compound

To a suspension of ethyl1-amino-5-cyano-4-(3-fluoro-4-nitrophenyl)-1H-pyrrole-3-carboxylate(19.8 g, 62.2 mmol) in EtOH (600 mL) was added formadine acetate (51.8g, 497.7 mmol). The reaction mixture was heated to 70° C. over night.The reaction was not complete so an additional portion of formadineacetate (10.0 g, 96.1 mmol) was added. The reaction mixture was heatedto 70° C. for an additional 8 h. The reaction mixture was cooled and theEtOH was removed under reduced pressure. The remaining solids weresuspended in H₂O (1 L). The suspension was filtered to provide the titlecompound (19.6 g, 56.76 mmol) as a yellow solid in 91% yield. ¹H-NMR(DMSO-d₆) δ 8.21 (s, 1H), 8.19 (app t, J=8.4 Hz, 1H), 7.98 (s, 1H), 7.66(dd, J=12.4, 2.0 Hz, 1H), 7.41 (m, 1H), 4.09 (q, J=7.2 Hz, 2H), 1.10 (t,J=7.2 Hz, 3H); LCMS RT=2.90 min; MS {M+H]⁺=346.0.

Intermediate D Preparation of methyl4-bromo-5-cyano-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,1-pyrrole-3-carboxylate

Step 1: Preparation of 4-(trichloroacetyl)-1H-pyrrole-2-carbonitrile

Trichloracetyl chloride (44.4 g, 27.3 mL, 244 mmol) in dichloromethane(75 mL) was added over 20 min to a mechanically stirred suspension ofaluminum trichloride (54.3 g, 407 mmol) in dichloromethane (150 mL). Theresulting mixture was stirred for 30 min, and then 2-cyanopyrrole (15.0g, 163 mmol) in dichloromethane (75 mL) was added over 30 min. Thereaction was heated at reflux for 5 h and then allowed to cool. Thereaction was diluted with ethyl acetate (600 mL) and then quenchedslowly with water (300 mL). The layers were separated and then theorganic layer was washed with water and brine, dried (magensium sulfate)and evaporated under reduced pressure to afford a quantitative yield ofdesired product (39.0 g, 100%) containing trace impurities. Thismaterial was used in the next step without further purification. ¹H NMR(DMSO-d₆) δ 8.14 (s, 1H), 7.55 (s, 1H).

Step 2: Preparation of methyl 5-cyano-1H-pyrrole-3-carboxylate

Sodium methoxide (17.8 g, 329 mmol) was added to a solution of4-(trichloroacetyl)-1H-pyrrole-2-carbonitrile (39.0 g, 164 mmol) inmethanol (350 mL). The reaction was stirred for 16 h and then themethanol was evaporated under reduced pressure. The residue wasdissolved in ethyl acetate (800 mL) and the solution was adjusted to pH6 using 1 M hydrochloric acid. The layers were separated and then theorganic layer was washed with water and brine, dried (magensium sulfate)and evaporated under reduced pressure to afford the expected product(24.2 g, 98%). ¹H NMR (DMSO-d₆) δ 7.76 (s, 1H), 7.28 (s, 1H), 3.72 (s, 3H).

Step 3: Preparation of methyl2,4-dibromo-5-cyano-1H-pyrrole-3-carboxylate

Bromine (54.1 g, 17.4 mL, 338 mmol) was added slowly (20 min) to acooled (0° C.) solution of methyl 5-cyano-1H-pyrrole-3-carboxylate (24.2g, 161 mmol) in 1 M aqueous sodium hydroxide solution (500 mL). The coldbath was removed and the reaction was stirred for 2 h. The reaction wasquenched by addition of 1 M hydrochloric acid (400 mL) and the resultingprecipitate was collected by filtration. The material was washed with 1M hydrochloric acid to give the desired product (44.8 g, 90%). ¹H NMR(DMSO-d₆) δ 3.77 (s, 3H).

Step 4: Preparation of methyl2,4-dibromo-5-cyano-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-pyrrole-3-carboxylate

Potassium carbonate (56.5 g, 409 mmol) was added to a 0° C. solution ofmethyl 2,4-dibromo-5-cyano-1H-pyrrole-3-carboxylate (42.0 g, 136 mmol)in dimethylformamide (250 mL). After gas evolution ceased,2-(chloromethoxy)ethyl](trimethyl)silane (34.1 g, 36.1 mL, 205 mmol) wasadded over 20 min. The reaction was stirred for 2 h and then poured intowater (3 L). The product was extracted with ethyl acetate (3×500 mL) andthen the combined organic extracts were washed with water, dried(magnesium sulfate) and evaporated under reduced pressure. The residuewas triturated with hexane to afford the desired product (44.1 g, 73%).¹H NMR (DMSO-d₆) δ 5.51 (s, 2H), 3.83 (s, 3H), 3.62, (t, J=7.9 Hz, 2H),0.91, (t, J=7.9 Hz, 2H), 0.00 (s, 9H).

Intermediate E Preparation of ethyl2,4-dibromo-5-cyano-1-{[2-(trimethyl-silyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate

The procedure used for the preparation of Intermediate D was used toprepare the title compound by substituting ethanol for methanol in step2.

Intermediate F Preparation of1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]ureaPreparation 1

Step 1: Preparation of2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

4-Bromo-2-fluoroaniline (45.00 g, 236.8 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (66.15 g,260.5 mmol, 1.1 eq) were added as solids to a flask then dissolved in1,4-dioxanes (250 mL) and placed under N₂. The reaction was takenthrough five purge-fill cycles using high vacuum and nitrogen. To thissolution was added potassium acetate (69.72 g, 710.4 mmol, 3 eq) and thereaction was again taken through three purge-fill cycles using highvacuum and nitrogen. To the reaction was added1,1′-bis(diphenylphosphino)ferrocene (5.20 g, 7.1 mmol, 0.03 eq). Thereaction was taken one final time through five purge-fill cycles usinghigh vacuum and nitrogen. The reaction was heated at 80° C. overnight(17 hr). After cooling to rt, EtOAc was added (1000 mL) and the reactionwas partitioned between EtOAc and water. The organic phase was washedwith brine, dried (Na₂SO₄), filtered, concentrated in vacuo. The crudematerial was dissolved in dichloromethane and the desired product (50.84g, 90.6% yield) was obtained after flash column chromatography (9:1Hexanes:EtOAc). ¹H-NMR (DMSO-d₆) δ 7.17 (dd, J=7.8, 1.4 Hz, 1H), 7.12(dd, 12.1, 1.2 Hz, 1H), 6.70 (t, 7.9 Hz, 1H) 5.56 (s, 2H), 1.22 (s,12H); MS [M+H]⁺=238, LCMS RT=3.35 min.

Step 2: Preparation of Title Compound

To a solution of2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (7.65 g,32.3 mmol, 1 eq) in 1,2-dichloroethane (76.5 mL) was added1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene (4.9 ml, 33.9 mmol,1.05 eq). The reaction was allowed to stir overnight. White solidsprecipitated from the reaction mixture and were filtered and washed withhexanes (3×). The solids were dried under vacuum to obtain 8.75 g (61.3%yield) of the desired product. ¹H-NMR (DMSO-d₆) δ 9.45 (d, J=2.7 Hz,1H), 9.32 (d, J=2.76 Hz, 1H), 8.63 (dd, J=7.2, 2.2 Hz, 1H), 8.28 (t,J=8.0 Hz, 1H), 7.50-7.34 (m, 4H), 1.27 (s, 12H); MS [M+H]⁺=443, LCMSRT=4.50 min

Intermediate F Preparation ofN-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]ureaPreparation 2

Step 1. Preparation ofN-(4-bromo-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a solution of 1,2 dichloroethane (100 mL) was added4-bromo-2-fluoroaniline (5.00 g, 26.31 mmol) followed by2-fluoro-5-trifluoromethyl phenylisocyante (5.67 g, 27.63 mmol) in oneportion. The solution was allowed to stir overnight at rt, and theresulting solids were filtered and rinsed with 1,2 dichloroethane (3×5mL). A second crop of product was obtained by concentrating the motherliquor and redissolving in 1,2 dichloroethane (20 mL) The solution wasbriefly heated to reflux and upon cooling the desired productprecipitated. The solid was filtered and rinsed with 1,2 dichloroethane(3×5 mL). Total amount of white solids obtained was 10.13 g (25.64 mmol,97.4% yield). ¹H-NMR (DMSO-d₆) δ 9.37 (s, 1H), 9.23 (s, 1H), 8.60 (d,J=7.2 Hz, 1H), 8.15 (t, J=8.8 Hz, 1H), 7.58 to 7.50 (dd, J=8.9, 2.2 1H),7.48 (m, 1H), 7.40 to 7.32 (m, 2H); LCMS RT=4.22 min.

Step 2: Preparation of Title Compound

To a solution of 1,4-dioxane (60 mL) was added Intermediate B(N-(4-bromo-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl urea)(10.00 g, 25.31 mmol). DMF was added dropwise until the solution washomogeneous a the reaction was degassed 3 times. To this solution wasadded bis(pinacolato)diboron (7.71 g, 30.37 mmol) in one portion. Thereaction was degassed 5 times and potassium acetate (7.45 g, 75.92 mmol)was then added in one portion. The reaction was again degassed 3 times.To this heterogeneous reaction was added1,1′-Bis(diphenylphosphino)ferrocenepalladium dichloride (925 mg, 1.26mmol) and the reaction was degassed 5 additional times and was thenheated at 80° C. overnight (17 hr). After cooling to rt, the reactionwas filtered through a thin pad of silica to remove solids and thenpurified via flash column chromatography (15:1 to 5:1 Hex:EtOAc) toafford the desired product as a white solid. (12.24 g, 27.68 mmol).¹H-NMR (DMSO-d₆) δ 9.46 (s, 1H), 9.33 (s, 1H), 8.63 (d, J=7.4 Hz, 1H),8.28 (t, J=8.2 Hz, 1H), 7.52 to 7.35 (br m, 4H), 1.27 (s, 12H); MS[M+H]⁺=443; LCMS RT=4.31 min.

Intermediate G Preparation ethyl4-amino-5-(4-amino-3-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylatehydrochloride

Step 1: Preparation of ethyl4-bromo-5-cyano-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-pyrrole-3-carboxylate

A solution of Intermediate E (ethyl2,4-dibromo-5-cyano-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate(42.10 g, 92.9 mmol)) in 1.0 L THF was cooled to −65 C and a solution ofn-butyllithium in hexanes (1.6M, 87.09 mL, 139.3 mmol) was addeddropwise over 20 min. After 15 additional minutes, the reaction wasquenched by addition of methanol (14.86 mL, 464 mmol). The reaction wasdiluted with Et₂O (1 L) and brine (200 mL). The organic layer wasseparated, dried (Na₂SO₄) and filtered through a plug of silica.Evaporation of the solvent afforded the title compound as a brown solid(33.91 g, 97.8% yield). ¹H-NMR (DMSO-d₆) δ 8.18 (s, 1H), 5.50 (s, 2H),4.28 (q, J=7 Hz, 2H), 3.55 (t, J=8 Hz, 2H), 1.32 (t, J=7 Hz, 2H), 0.89(t, J=8 Hz, 2H), 0.00 (s, 9H); GCMS [M+H]⁺=372.9; GCMS RT=5.43. LCMSRT=3.94.

Step 2: Preparation of ethyl4-{4-[(tertbutoxycarbonylamino]-3-fluorophenyl}-5-cyano-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate

A degassed suspension of palladium(II) acetate (1.86 g, 8.304 mmol) indioxane (20 mL) was treated with triphenylphosphine (8.71 g, 33.2 mmol)and the mixture allowed to stir for 15 min. The yellow suspension wasthen diluted with dioxane (500 mL) and treated with ethyl4-bromo-5-cyano-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-pyrrole-3-carboxylate(31.70 g, 83.04 mmol) and Intermediate F(t-butyl[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate(27.83 g, 87.19 mmol)). The solution was degassed and backfilled with N₂(2×) before treatment with aqueous sodium carbonate (2 N, 83.04 mL,166.1 mmol). The reaction mixture was again degased and backfilled withN₂ (2×) then heated to 80 C for 16 h. The reaction mixture was cooled tort and diluted with EtOAc (200 mL) and hexanes (200 mL). After washingwith sodium bicarbonate (1×) and brine (1×) the organic layer wasfiltered passed through a large pad of silica gel. Evaporation of thesolvent gave the title compound as a viscous, semi-solid (31.0 g,75.2%). ¹H-NMR (DMSO-d₆) δ 9.15 (s, 1H), 8.14 (1H), 7.71 (t, J=8 Hz,1H), 7.31 (dd, J=12, 2 Hz, 1H), 7.21 (dd, J=8, 2 Hz, 1H), 5.50 (s, 1H),4.16 (q, J=7 Hz, 2H), 3.59 (t, J=8 Hz, 2H), 1.20 (t, J=7 Hz, 3H), 1.50(s, 9H), 0.90 (t, J=8 Hz, 2H), 0.00 (s, 9H); MS [M+Na]⁺=526.4; LCMSRT=4.09.

Step 3: Preparation of ethyl4-{4-[(tert-butoxycarbonyl)amino]-3-fluorophenyl}-5-cyano-1H-pyrrole-3-carboxylate

Ethyl4-{4-[(tertbutoxycarbonylamino]-3-fluorophenyl}-5-cyano-1-{[2-(trimethyl-silyl)-ethoxy]methyl}-1H-pyrrole-3-carboxylate(31.00 g, 63.8 mmol) was taken up in 400 mL solution oftert-butylammonium fluoride in THF (1 N, 400 mL, 400 mmol) which hadbeen dried with activated 3 A MS. After 10 min the reaction appearedcomplete by TLC. The reaction was diluted with EtOAc and washed withaqueous 1 N Na₂HPO₄ (1×) and water (3×). The organic layer was driedwith Na₂SO₄, filtered thru a plug of silica and concentrated to afford afaintly orange solid. The solids were trituration with ether:hexanes(1:3) to provided the title compound as a yellowish solid free ofimpurities (20.13 g, 88.7% yield) ¹H-NMR (DMSO-d₆) δ 9.07 (s, 1H), 7.01(s, 1H), 7.62 (t, J=8 Hz, 1H), 7.26 (dd, J=12, 2 Hz, 1H), 7.16 (dd, J=9,2 Hz, 1H), 4.10 (q, J=7 Hz, 2H), 1.45 (s, 9H), 1.14 (t, J=7 Hz, 3H); MS[M+Na]⁺=395.9; LCMS RT=3.45.

Step 4: Preparation of ethyl1-amino-4-{4-[(tert-butoxycarbonyl)amino]-3-fluorophenyl}-5-cyano-1H-pyrrole-3-carboxylate

A 1-L 3-neck rbf was fitted with an overhead stirrer and charged withsodium hydride (60% dispersion in mineral oil, 2.19 g, 54.6 mmol) andDMF (550 mL). Ethyl4-{4-[(tert-butoxycarbonyl)amino]-3-fluorophenyl}-5-cyano-1H-pyrrole-3-carboxylate(10.00 g, 45.5 mmol) was added and the mixture was left to stir at rtfor 15 min. The reaction mixture was treated with (aminooxy)(diphenyl)phosphine oxide (12.74 g, 54.6 mmol) and heated to 60° C. The very thickreaction mixture gradually became a readily stirred suspension. After 1h analysis by RP-HPLC indicated that all starting material had beenconsumed. The reaction was cooled to rt and diluted with 1.5 L EtOAc andaq. sodium bicarbonate. The aqueous layer was back extracted with EtOAc(2×) and the combined organic layers were dried (sodium sulfate) andfiltered through a silica plug. Trituration with ether:hexanes (1:2)gave the title compound as a yellowish powder (18.06 g, 46.5 mmol,93.7%). ¹H-NMR (DMSO-d₆) δ 9.13 (s, 1H), 7.68 (s, 1H, 7.68 (t, J=8 Hz,1H), 7.29 (dd, J=12, 2 Hz, 1H), 7.19 (dd, J=8 Hz, 1H), 6.67 (s, 2H),4.14 (q, J=7 Hz, 2H), 1.50 (s, 9H), 1.18 (s, 3H); MS [M+Na]⁺=411.0; LCMSRT=3.48.

Step 5: Preparation of ethyl4-amino-5-{4-[(tert-butoxycarbonyl)amino]-3-fluorophenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate

A mixture of ethyl1-amino-4-{4-[(tert-butoxycarbonyl)amino]-3-fluorophenyl}-5-cyano-1H-pyrrole-3-carboxylate(18.06 g, 46.5 mmol), formamidine acetate (48.41 g, 464.9 mmol) andfinely ground potassium phosphate (19.74 g, 93.0 mmol) in ethanol (350mL) was heated at 80° C. overnight. After 16 h, the reaction mixture wascooled to rt and diluted with 1.8 L water. The resulting precipitate wasfiltered thru a glass frit and washed with water. Drying in a vacuumoven provided the title compound as a gray solid (15.6 g, 80.8%) ¹H-NMR(DMSO-d₆) δ 9.11 (s, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 7.72 (t, J=8 Hz,1H), 7.26 (dd, J=12, 2 Hz, 1H), 7.12 (dd, J=8, 2 Hz, 1H), 4.07 (q, J=7Hz, 2H), 1.47 (s, 9H), 1.09 (t, J=7 Hz, 3H); MS [M+H]⁺ 415.8=;. LCMSRT=3.05.

Step 6: Preparation of Title Compound

A suspension of ethyl4-amino-5-{4-[(tert-butoxycarbonyl)amino]-3-fluorophenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate(400 mg, 0.963 mmol) in 4 N HCl in dioxane (9.63 mL, 38.5 mmol) washeated to 60° C. for 5 min, then cooled to rt and diluted with 40 mLether. Filtration through a teflon membrane filter gave the titlecompound as a yellow solid (310 mg, 91.5% yield). ¹H-NMR (DMSO-d₆) δ8.33 (s, 1H), 8.14 (s, 1H), 7.16 (d, J=12 Hz, 1H), 6.96 to 7.03 (m, 2H),4.13 (q, J=8 Hz, 2H), 1.15 (t, J=8 Hz, 3H); MS [M+H]⁺=316.1; LCMSRT=2.39.

Intermediate H Preparation of ethyl4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate

Raney nickel (several spatulas) was added to a flask containing 20 mL ofEtOH. The catalyst was triturated with abs EtOH (3×20 mL). A suspensionof Intermediate B (ethyl4-amino-5-(4-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate(4.0 g, 12.2 mmol)) in abs EtOH (600 mL)/THF (200 mL) was added to theflask with the catalyst. The flask was evacuated and refilled withhydrogen gas (3×) and the reaction was then placed under a hydrogenatmosphere (1 atm) and allowed to stir at rt overnight. The reaction wasfiltered through a Celite® pad and washed with copious amounts ofEtOH/THF (3:1) to afford 3.60 g of the above compound as a brown solid(yield 96%) ¹H-NMR (DMSO-d₆) δ 8.05 (s, 1H), 8.04 (br s, 2H), 7.88 (s,1H), 7.01 (d, J=8.0 Hz, 2H), 6.61 (d, J=8.0 Hz, 2H), 5.31 (br s, 2H),4.07 (q, J=7.4 Hz, 2H), 1.12 (t, J=7.2 Hz, 3H); MS [M+H]⁺=298; LCMSRT=1.64 min; TLC R_(f)=0.30 (Acetone/CH₂Cl₂ 1:3).

Intermediate I Preparation of ethyl4-amino-5-(4-amino-3-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate

The procedure used for the preparation of Intermediate H was used toprepare the title compound by substituting Intermediate C forIntermediate B. ¹H-NMR (DMSO-d₆) δ 8.07 (s, 1H), 7.90 (s, 1H), 7.04 to7.01 (d, J=12.3 Hz, 1H), 6.88 to 6.85 (m, 2H), 6.81 to 6.77 (m, 1H),5.36 (s, 2H), 4.11 to 4.06 (q, J=7.1 Hz, 2H), 1.15 to 1.11 (t, J=7.0 Hz,3H); MS [M+H]⁺=316.1; LCMS RT=2.16 min.

Intermediate J Preparation of ethyl4-amino-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f]-[1,2,4]triazine-6-carboxylate

To a solution of DCE (200 mL) was added intermediate H (ethyl4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate(6.40 g. 21.5 mmol)) followed by 2-fluoro-5-(trifluoromethyl)phenylisocyanate (6.38 mL, 44.13 mmol). The solution was heated at 80° C. for17 h. To the reaction mixture was added DMF (200 mL) and aq 2 N HCl(10.8 mL, 21.5 mmol), and the solution was heated to 80° C. for 2.5 h.The reaction mixture was evaporated under reduced pressure and thentriturated with THF/Et₂O. A white solid formed which was collected andwashed with Et₂O. Upon drying under vacuum 9.14 g of product wasisolated (18.2 mmol, 85%). ¹H-NMR (DMSO-d₆) δ 9.33 (s, 1H), 8.97 (d,J=4.0 Hz, 1H), 8.62 (d, J=12.0 Hz, 1H), 8.12 (s, 1H), 8.11 (br s, 1H),7.92 (s, 1H), 7.6-7.3 (m, 5H), 4.10 (q, J=8.0 Hz, 2H), 1.11 (t, J=8.0Hz, 3H); MS [M+H]⁺=503; LCMS RT=3.50 min; TLC R_(f)=0.40 (3:1 v/vCH₂Cl₂-Acetone).

Intermediate K Preparation ofN-{4-[4-amino-6-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a solution of THF (8.0 mL) was added Intermediate J (80.0 mg, 0.16mmol) followed by DIBAL (0.8 mL, 0.8 mmol, 1.0M solution in THF). Thereaction was stirred at rt with addition of DIBAL (2.4 mL, 2.4 mmol,1.0M solution in THF) in three batches until HPLC indicated completionof reaction. The reaction was diluted with EtOAc and quenched withsaturated aqueous Rochelle's salt. Reaction was extracted with EtOAc(4×). Organic was dried (Na₂SO₄) and evaporated to give a crude oil thatwas purified via HPLC (10-90% ACN/H₂O) yielding a yellow solid (40.0 mg,55%). ¹H-NMR (CD₃CN) δ 8.61 (d, J=8.0 Hz, 1H), 7.80 (s, 1H), 7.66-7.60(m, 3H), 7.42-7.32 (m, 4H), 4.50 (s, 2H); MS [M+H]⁺=461; LCMS RT=2.87min

Intermediate L Preparation of ethyl4-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate

The procedure used for the preparation of Intermediate J was used toprepare the title compound by substituting Intermediate I forIntermediate H. ¹H-NMR (DMSO-d₆) δ 9.42 (s, 1H), 9.28 (s, 1H), 8.65 to8.63 (m, 1H), 8.27 to 8.22 (m, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 4.11 to4.06 (m, 2H), 1.14 to 1.10 (m, 3H); MS [M+H]⁺=521.3; LCMS RT=2.98 min.

Intermediate M Preparation ofN-{4-[4-amino-6-(hydroxymethyl)pyrrolo-[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

The procedure used for the preparation of Intermediate K was used toprepare the title compound by substituting Intermediate L forIntermediate J. ¹H-NMR (DMSO-d₆) δ 9.41 (s, 1H), 9.40 (s, 1H), 9.26 to8.63 (m, 1H), 8.28 to 8.24 (m, 1H), 7.83 (s, 1H), 7.66 (s, 1H), 7.53 to7.48 (m, 1H), 7.41 to 7.33 (m, 2H), 7.18 (d, J=8.2 Hz, 1H), 5.01 to 4.98(m, 1H), 4.37 (d, J=5.0 Hz, 2H); MS [M+H]⁺=479.1; LCMS RT=2.49 min.

Intermediate N Preparation ofN-[4-(4-amino-6-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Intermediate M(N-{4-[4-amino-6-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluoro-phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea)(1.02 g, 2.13 mmol) was dissolved in THF (500 mL) and to it was addedDess-Martin Periodinane reagent (0.99 g, 2.35 mmol). The reaction wasstirred at rt for 1 h. The reaction was then diluted with EtOAc andsaturated aqueous NaHCO₃/Na₂S₂O₃ 1:1 which was stirred for 30 min andthen transferred to a separatory funnel. The organic layer was washedwith aqueous NaHCO₃/Na₂S₂O₃ 1:1 and water. The organic layer was dried(MgSO₄), filtered, and evaporated to give 0.99 g of product (2.10 mmol,98%). ¹H-NMR (DMSO-d₆) δ 9.75 (s, 1H), 9.45 (s, 1H), 9.33 (s, 1H), 8.65to 8.64 (d, J=7.1 Hz, 1H), 8.34 to 8.29 (m, 2H), 7.97 (s, 1H), 7.54 to7.40 (m, 3H), 7.27 to 7.25 (d, J=9.4 Hz, 1H); MS [M+H]⁺=477.1; LCMSRT=3.07 min.

Intermediate O Preparation ofN-{4-[4-amino-6-(1,3-oxazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

To a solution of MeOH (20 mL), THF (20 mL), and 0.5 M sodium methoxidein MeOH (6.30 mL, 3.15 mmol) cooled in an ice bath was added tosylmethylisocyanide (0.61 g, 6.30 mmol) and Intermediate N(N-[4-(4-amino-6-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoro-methyl)phenyl]urea(500 mg, 1.05 mmol)). The solution was allowed to stir at 0° C. for 5min and was then heated to 60° C. for 6 h. Upon cooling to rt, thesolution was partially evaporated and a solid formed which was collectedand washed with MeOH. The solid was dried under vacuum producing 140 mgof white powder (0.27 mmol, yield 26%). ¹H-NMR (DMSO-d₆) δ 9.46 (s, 1H),9.32 (s, 1H), 8.65 to 8.64 (d, J=7.4 Hz, 1H), 8.35 to 8.30 (t, J=8.5 Hz,1H), 8.30 (s, 1H), 8.09 (s, 1H), 7.90 (s, 1H), 7.53 to 7.48 (m, 1H),7.42 to 7.39 (m, 1H), 7.37 to 7.34 (d, J=12.0 Hz, 1H), 7.21 to 7.19 (d,J=8.4 Hz, 1H), 6.62 (s, 1H); MS [M+H]⁺=516.1; LCMS RT=3.01 min.

Intermediate P Preparation ofN-[4-(4-amino-6-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Intermediate K(N-{4-[4-amino-6-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea(40.0 mg, 0.09 mmol)) was dissolved in THF (5.0 mL) and to it was addedDess-Martin Periodinane reagent (44.0 mg, 0.10 mmol). The reaction wasstirred at rt until HPLC indicated completion of reaction. Reaction wasdiluted with EtOAc and washed with saturated aqueous NaHCO₃/Na₂S₂O₃ 1:1(3×). The aqueous layer was back extracted with EtOAc (2×). The combinedorganic layer was dried (Na₂SO₄) and evaporated to give a crude oil thatwas purified via HPLC (10-90% ACN/H₂O) to give a yellow solid (35.0 mg,88%). ¹H-NMR (CD₃OD) δ 9.76 (s, 1H), 8.61 (d, J=8.0 Hz, 1H), 8.11 (s,1H), 7.87 (s, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.30(d, J=8.0 Hz, 1H); MS [M+H]⁺=459; LCMS RT=2.95 min.

Intermediate Q Preparation ofN-{4-[4-amino-6-(1,3-oxazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Intermediate O was used toprepare the title compound by substituting Intermediate P forIntermediate N. ¹H-NMR (CD₃OD) δ 8.63 (d, J=6.8 Hz, 1H), 8.13 (s, 1H),7.98 (s, 1H), 7.83 (s, 1H), 7.69 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.4 Hz,2H), 7.35 (d, J=8.3 Hz, 2H), 6.49 (s, 1H); MS [M+H]⁺=498.1; LCMSRT=2.82.

Intermediate R Preparation ofN-[4-(4-amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a solution of pyridine (40 mL) was added Intermediate P(N-[4-(4-amino-6-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea(2.64 g, 5.76 mmol)) followed by hydroxylamine hydrochloride (0.63 g,6.33 mmol). The reaction was stirred at ambient temperature for 1 h, andthen acetic anhydride (1.20 mL, 12.67 mmol) was added. The solution washeated at 80° C. for 1 h. Additional acetic anhydride (0.27 mL, 2.88mmol) was added and the solution was heated at 80° C. for 1 h. Uponcooling to rt, the solution was concentrated to half the original volumein vacuo, and subsequently EtOAc (100 mL) and aq NaHCO₃ (100 mL) wereadded to the reaction, which was then transferred to a separatoryfunnel. The organic layer was collected and washed with water (50 mL).The aqueous layer was back extracted with EtOAc, which was washed withwater. The organic layers were combined, dried (MgSO₄), filtered,concentrated to dryness, and purified by flash chromatography (9:1 v/vCH₂Cl₂-MeOH). The resulting purified fractions were combined andtriturated in EtOH. The material was washed with cold EtOH and driedunder vacuum yielding 1.45 g of a pale yellow solid (3.18 mmol, yield55%). ¹H-NMR (CD₃OD) δ 8.62 (d, J=7.0 Hz, 1H), 8.19 (s, 1H), 7.91 (s,1H), 7.69 (d, J=8.6 Hz, 2H), 7.50 (d, J=8.6 Hz, 2H), 7.34 (d, J=8.7 Hz,2H); MS [M+H]⁺=456.1; LCMS RT=3.10.

Intermediate S Preparation of4-amino-5-{4-[({[2-fluoro-5-(trifluoromethyl)-phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylicacid

To a solution of Intermediate J (720.0 mg, 1.433 mmol) in MeOH (5 mL)and THF (3 mL) was added 1 M NaOH (3.58 mL, 3.58 mmoL) and the reactionleft to stir at 60° C. for 12 h. The reaction mixture was cooled andpartitioned between CHCl₃ and pH 2 sulfate buffer. The organic layer waswashed with brine, dried (Na₂SO₄) and concentrated to yield a brownsolid (623 mg, 92% yield). ¹H-NMR (DMSO-d₆) δ 12.17 (bs, 1H), 9.34 (s,1H), 8.98 (d, J=2 Hz, 1H), 8.62 (dd, J=2 Hz, 8 Hz, 1H), 8.07 (3, 1H),8.0 (bs, 1H), 7.91 (s, 1H), 7.53 (d, J=8 Hz, 2H), 7.55-7.45 (m, 1H),7.42-7.35 (m, 1H), 7.32 (d, J=8 Hz, 2H), 5.0 (bs, 1H); MS [M+H]⁺=475.2;LCMS RT=2.56 min; TLC R_(f)=0.26 (1:1:0.02 v/v/v THF:CH₂Cl₂:MeOH).

Intermediate T Preparation of4-amino-5-{4-[({[2-fluoro-5-(trifluoro-methyl)phenyl]amino}carbonyl)amino]phenyl}-N-(2,2,2-trifluoroethyl)-pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide

To a solution of Intermediate S (2.92 g, 6.16 mmol) in DMF (100 mL) wasadded benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (2.72 g, 6.16 mmol), 4-methylmorpholine (0.68 ml,6.16 mmol), and 2,2,2-trifluoroethylamine (0.48 mL, 6.16 mmol). Thesolution was allowed to stir at rt for 17 h. The crude reaction mixturewas reduced in vacuo and purified by flash column chromatography(50:45:5 v/v/v CH₂Cl₂-EtOAc-MeOH). The purified fractions were combinedand triturated with CH₂Cl₂/hexanes. The white solid was collected andwashed with hexanes and upon drying under vacuum yielded 2.18 g (3.92mmol, 64% yield). ¹H-NMR (DMSO-d₆) δ 9.29 (s, 1H), 8.93 (s, 1H),8.64-8.58 (m, 1H), 8.51 (t, J=6 Hz, 1H), 8.18 (s, 1H), 8.00 (bs, 1H),7.91 (s, 1H), 7.52 (d, J=8 Hz, 2H), 7.51 to 7.46 (m, 1H), 7.40 to 7.30(m, 1H), 7.28 (d, J=8 Hz, 2H), 5.05 (bs, 1H), 4.00 to 3.85 (m, 2H). MS[M+H]⁺=556.2; LCMS RT=3.32 min; TLC R_(f)=0.33 (2:1 v/v CH₂Cl₂-THF).

Intermediate U Preparation of4-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylicacid

The procedure used for the preparation of Intermediate S was used toprepare the title compound by substituting Intermediate L forIntermediate J. ¹H-NMR (DMSO-d₆) δ 12.3 (s, 1H), 9.43 (s, 1H), 9.27 (s,1H), 8.65 to 8.63 (m, 1H), 8.25 to 8.20 (m, 1H), 8.07 (s, 1H), 8.02 (s,1H); MS [M+H]⁺=433.1; LCMS RT=2.58 min.

Intermediate V Preparation ofphenyl[4-(trifluoromethyl)pyridin-2-yl]carbamate

A solution of the commerically available2-amino-4-trifluoromethylpyridine (20.86 g, 128.7 mmol) in 250 mL CH₂Cl₂was treated with phenylchloroformate (17.81 mL, 141.5 mmol) and pyridine(22.85 mL, 283 mmol). During addition of the pyridine a yellowprecipitate formed and a considerable exotherm was observed. After 0.5 hthe homogeneous reaction was diluted with 1 L Et₂O and washed with 1 Nbisulfate buffer (pH 2) and sat. NaHCO₃. The organic layer was driedwith Na₂SO₄ and evaporated to yield a gray solid. Trituration withEt₂O:hexanes (1:5) gave the title compound as white crystals (33.5 g,92% Yield). ¹H-NMR (DMSO-d₆) δ 11.28 (s, 1H), 8.60 (d, J=5.1 Hz, 1H),8.12 (bs, 1H), 7.40 to 7.48 (m, 3H), 7.22 to 7.31 (m, 3H); MS[M+H]⁺=283.1; LCMS RT=3.51.

Intermediate W Preparation of ethyl4-amino-5-{4[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate

To a solution of THF (100 mL) was addedphenyl[4-(trifluoromethyl)pyridin-2-yl]carbamate (1.27 g, 4.48 mmol),Intermediate H (ethyl4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate(1.33 g, 4.48 mmol)) and triethylamine (0.63 mL, 4.48 mmol). Thesolution was heated at 60° C. for 3 h. Upon cooling to rt the solutionwas triturated with THF/Et₂O. The precipitate was collected and washedwith Et₂O. Upon drying under vacuum 1.65 g of product was isolated (3.40mmol, 76%). ¹H-NMR (DMSO-d₆) δ 10.19 (s, 1H), 9.89 (s, 1H), 8.52 (d,J=5.4 Hz, 1H), 8.12 (s, 1H), 8.12 to 8.10 (m, 2H), 7.93 (s, 1H), 7.59(d, J=6.9 Hz, 2H), 7.48 to 7.30 (m, 3H), 5.15 to 5.10 (m, 1H), 4.06 (q,J=7.2 Hz, 2H), 1.11 (t, J=7.2 Hz, 3H); MS [M+H]⁺=486.1; LCMS RT=3.33min; TLC R_(f)=0.27 (3:7 v/v THF-CH₂Cl₂).

Intermediate X Preparation of4-amino-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylicacid

The procedure used for the preparation of Intermediate S was used toprepare the title compound by substituting Intermediate W forIntermediate J. ¹H-NMR (DMSO-d₆) δ 12.3 (s, 1H), 9.87 (s, 1H), 9.75 (s,1H), 8.53 (d, J=5.3 Hz, 2H), 8.07 to 8.06 (m, 3H), 7.86 (s, 1H), 7.58 to7.56 (m, 2H), 7.36 to 7.33 (m, 3H); MS [M+H]⁺=458.0; LCMS RT=2.28 min.

Intermediate Y Preparation ofN-{4-[4-amino-6-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

Intermediate W (0.25 g, 0.515 mmol) was suspended in THF (5 mL) andtreated with 1 M solution of MAL in THF (2 mL, 2.06 mmol). The resultingsolution was stirred at room temperature for 3 hours and quenched withsaturated NH₄Cl solution. The mixture was stirred for 1 hour. Themixture was transferred to a sep. funnel and the crude product wasextracted with EtOAc. The organic layer was then washed with water andsaturated NaCl solution. The organic layer was then dried over MgSO₄,filtered and concentrated under reduced pressure. The remaining solidwas then triturated with EtOAc and filtered providing 0.22 g of productas a tan solid (0.496 mmol, 96% yield). ¹H-NMR (DMSO) δ 11.66 (s, 1H),9.86 (s, 1H), 9.73 (s, 1H), 8.53 (d, J=8.7 Hz, 1H), 8.05 (s, 1H), 7.82(s, 1H), 7.65 (s, 1H), 7.61 (d, J=6.6 Hz, 2H), 7.38-7.35 (m, 3H), 4.95(t, J=5.2 Hz, 1H), 4.37 (d, J=5.1 Hz, 2H); MS [M+H]⁺=444.0; LCMS RT=2.3min.

Intermediate Z Preparation ofN-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

To a solution of THF (200 mL) was added Intermediate Y(N-{4-[4-amino-6-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)-pyridin-2-yl]urea(1.77 g, 3.98 mmol)) followed by 2M thionyl chloride in CH₂Cl₂ (19.9 mL,39.8 mmol). The reaction was stirred at ambient temperature for 30 min,and then concentrated by rotary evaporation chasing with CH₂Cl₂. Thereaction material was diluted with MeOH (100 mL) and triethyl amine(1.67 mL, 11.9 mmol) was added. The solution was heated at 60° C. for 1h. Upon cooling to rt, the solution was concentrated in vacuo andpurified by flash column chromatography (5:4:1 v/v/v CH₂Cl₂-EtOAc-MeOH).The resulting purified fractions were combined and evaporated to drynessproducing 1.14 g of a pale yellow solid (2.49 mmol, yield 63%). ¹H-NMR(CD₃OD) δ 8.52 (d, J=5.4 Hz, 1H), 7.79 (s, 1H), 7.76 (s, 1H), 7.71 to7.67 (m, 3H), 7.43 (d, J=8.6 Hz, 2H), 7.28 (d, J=5.3 Hz, 1H), 4.36 (s,2H), 3.29 (s, 3H); MS [M+H]⁺=458.1; LCMS RT=2.66.

Intermediate AA Preparation ofN-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of intermediate Z was used toprepare the title compound by substituting Intermediate K forIntermediate Y. ¹H-NMR (CD₃OD) δ 8.61 (d, J=7.6 Hz, 1H), 7.78 (s, 1H),7.68 (s, 1H), 7.62 (d, J=8.7 Hz, 2H), 7.40 (d, J=8.6 Hz, 2H), 7.33 (d,J=8.7 Hz, 2H), 4.35 (s, 2H), 3.30 (s, 3H); MS [M+H]⁺=475.2; LCMSRT=2.81.

Intermediate AB Preparation ofN-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

The procedure used for the preparation of Intermediate Z was used toprepare the title compound by substituting Intermediate M forIntermediate Y. ¹H-NMR (CD₃OD) δ 8.65 (d, J=8.0 Hz, 1H), 8.31 to 8.27(m, 1H), 7.80 (s, 1H), 7.70 (s, 1H), 7.35 to 7.23 (m, 4H), 4.37 (s, 2H),3.33 (s, 3H); MS [M+H]⁺=493.1; LCMS RT=2.84 min.

Intermediate AC Preparation ofN-{4-[4-amino-6-(cyanomethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

Thionyl chloride (0.31 mL, 4.18 mmol) was added dropwise to a vigorouslystirring slurry of Intermediate M (1.00 g, 2.09 mmol) in THF (20 mL) andCH₂Cl₂ (20 mL). The reaction mixture was allowed to stir for 30 minwhere upon HPLC indicated that the reaction was complete. The reactionwas concentrated and re-suspended in dichloroethane (3×). The resultinglight brown powder was dissolved in 20 mL of DMSO and the NaCN (512.1mg, 10.45 mmol) was added as a fine powder. The solution was sonicatedfor 10 minutes after which, HPLC indicated the reaction was complete.The reaction was diluted with 10 volumes of EtOAc and the organic layerwas washed with H₂O (3×). The organic layer was dried over Na₂SO₄ andconcentrated to give a light brown powder (933.0 mg, 1.91 mmol, 91%).(DMSO-d₆). δ 9.50 (d, J=3 Hz, 1H), 9.37 (d, J=2 Hz, 1H), 8.71 (dd, J=3,7.2 Hz, 1H), 7.94 (s, 1H), 7.82 (s, 1H), 7.60-7.53 (m, 1H), 7.50-7.44(m, 1H), 7.40 (dd, J=2, 12.6 Hz, 1H), 7.24 (dd, J=2, 8.4 Hz, 1H), 3.92(s, 2H). MS [M+H]⁺=488; LCMS RT=3.10 min.

Intermediate AD Preparation ofN-{4-[4-amino-6-(cyanomethyl)pyrrolo[2,1-f]-[1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Intermediate AC was used toprepare the title compound by substituting Intermediate K forIntermediate M. ¹H-NMR (DMSO-d₆) δ 9.41 (s, 1H), 9.01 (d, J=3 Hz, 1H),8.62 (d, J=3, 8 Hz, 1H), 7.81 (s, 1H), 7.77 (s, 1H), 7.61 (d, J=9 Hz,2H), 7.47 to 7.54 (m, 1H), 7.38 to 7.42 (m, 1H), 7.35 (d, J=9 Hz, 2H),5.35 (dd, J=2, 6 Hz), 3.82 (s, 2H); MS [M+H]⁺=470.1; LCMS RT=2.80 min.

Intermediate AE Preparation ofN-{4-[4-amino-6-(cyanomethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Intermediate AC was used toprepare the title compound by substituting Intermediate Y forIntermediate M. ¹H-NMR (DMSO-d₆) δ 8.54 (d, J=5 Hz, 1H), 8.07 (s, 1H),7.87 (s, 1H), 7.77 (s, 1H), 7.66 (d, J=9 Hz, 2H), 7.36 (d, J=9 Hz, 2H),7.34 to 7.36 (m, 1H), 3.81 (s, 2H); MS [M+H]⁺=453.1; LCMS RT=2.67 min.

Intermediate AF Preparation ofN-[4-(4-amino-6-formylpyrrolo[2,1-f][1,2,4]-triazin-5-yl)phenyl]-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

Intermediate Y (1.9 g, 4.29 mmol) was suspended in THF (20 mL) andtreated with Dess-Martin periodinane (2.0 g, 4.71 mmol). The mixture wasstirred at room temperature overnight and quenched with saturated NHCO₃solution with Na₂S₂O₃. The mixture was stirred for 1 hour thentransferred to a sep. funnel. The crude product was extracted with EtOAcand washed with water and saturated NaCl solution. The organic layer wasthen dried over MgSO₄, filtered and concentrated under reduced pressure.The remaining solid was then triturated with EtOAc and filteredproviding 1.8 g of product as a tan solid (4.08 mmol, 95% yield). ¹H-NMR(DMSO) δ 10.05 (bs, 1H), 9.82 (s, 1H), 9.72 (s, 1H), 8.52 (d, J=5.1 Hz,1H), 8.26 (s, 1H), 8.07 (s, 1H), 7.95 (s, 1H), 7.64 (d, J=8.6 Hz, 2H),7.44 (d, J=8.6 Hz, 2H), 7.35 (d, J=5.8 Hz, 1H); MS [M+H]⁺=442.0; LCMSRT=2.81 min.

Intermediate AG Preparation ofN-{4-[4-amino-6-(1,3-oxazol-5-yl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Intermediate O was used toprepare the title compound by substituting Intermediate AF forIntermediate N. ¹H-NMR (CD₃OD) δ 8.50 (d, J=5.3 Hz, 1H), 8.12 (s, 1H),7.98 (s, 1H), 7.84 (s, 1H), 7.77 (s, 1H), 7.76 (d, J=8.1 Hz, 2H), 7.45(d, J=8.0 Hz, 2H), 7.29 (d, J=6.3 Hz, 1H), 6.51 (s, 1H); MS[M+H]⁺=481.0; LCMS RT=2.70.

Intermediate AH Preparation of4-amino-N-(2,2,2-trifluoroethyl)-5-{-4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide

The procedure used for the preparation of Intermediate T was used toprepare the title compound by substituting Intermediate X forIntermediate S. ¹H-NMR (CD₃OD) δ 8.54 (d, J=5.1 Hz, 1H), 8.19 (s, 1H),8.06 (br s, 1H), 7.91 (s, 1H), 7.60 (d, J=8.7 Hz, 2H), 7.35 (d, J=5.6Hz, 2H), 7.31 (d, J=8.9 Hz, 2H), 3.94 (q, J=9.2 Hz, 2H); MS[M+H]⁺=539.0; LCMS RT=2.77.

Intermediate AI Preparation of ethyl4-amino-5-{3-fluoro-4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate

The procedure used for the preparation of Intermediate W was used toprepare the title compound by substituting Intermediate I forIntermediate H. ¹H-NMR (DMSO-d₆) δ 10.14 (s, 1H), 10.11 to 10.04 (br s,1H), 8.54 to 8.53 (d, J=5.3 Hz, 1H), 8.28 to 8.23 (t, J=8.4 Hz, 1H),8.14 (s, 1H), 8.01 (s, 1H), 7.94 (s, 1H), 7.39 to 7.33 (m, 2H), 7.18 to7.16 (d, J=10.0 Hz, 1H), 4.12 to 4.06 (q, J=8.3 Hz, 2H), 1.14 to 1.10(t, J=7.1 Hz, 3H); MS [M+H]⁺=504.1; LCMS RT=3.12 min.

Intermediate AJ Preparation ofN-{4-[4-amino-6-(hydroxymethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Intermediate Y was used toprepare the title compound by substituting Intermediate AI forIntermediate W. ¹H-NMR (DMSO-d₆) δ 10.13 (s, 1H), 10.07 to 10.02 (br s,1H), 8.54 to 8.53 (d, J=5.3 Hz, 1H), 8.29 to 8.24 (t, J=8.5 Hz, 1H),8.03 (s, 1H), 7.84 (s, 1H), 7.67 (s, 1H), 7.39 (s, 1H), 7.38 to 7.35 (d,J=8.7 Hz, 1H), 7.21 to 7.19 (d, J=9.7 Hz, 1H), 5.02 to 5.00 (t, J=5.1Hz, 1H), 4.39 to 4.37 (d, J=5.2 Hz, 2H); MS [M+H]⁺=462.0; LCMS RT=2.44min.

Intermediate AK Preparation ofN-{4-[4-amino-6-(1,3-oxazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

Step 1: Preparation ofN-[4-(4-amino-6-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Intermediate AF was used toprepare the title compound by substituting Intermediate AJ forIntermediate Y. ¹H-NMR (DMSO-d₆) δ 10.16 (s, 1H), 10.13 to 10.08 (br s,1H), 9.76 (s, 1H), 8.55 to 8.54 (d, J=5.3 Hz, 1H), 8.34 to 8.29 (t,J=8.6 Hz, 1H), 8.28 (s, 1H), 8.01 (s, 1H), 7.97 (s, 1H), 7.48 to 7.45(d, J=11.2 Hz, 1H), 7.39 to 7.38 (d, J=5.7 Hz, 1H), 7.29 to 7.27 (d,J=8.1 Hz, 1H); MS [M+H]⁺=459.9; LCMS RT=2.96 min.

Step 2: Preparation of Title Compound

To a solution of THF (10 mL) and MeOH (10 mL) cooled in an ice/waterbath was added 0.5 M sodium methoxide in MeOH (0.96 mL, 0.48 mmol)followed by TosMIC (93 mg, 0.48 mmol). The solution was allowed to stirfor 5 min and thenN-[4-(4-amino-6-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[4-(trifluoromethyl)pyridin-2-yl]urea(73 mg, 0.16 mmol) was added. The solution was heated to 60° C. for 17h. The reaction mixture was allowed to cool and was transferred to aseparatory funnel, diluted with EtOAc (20 mL), washed with aq saturatedNaHCO₃ (20 mL) and H₂O (20 mL). The aqueous layer was back extractedwith EtOAc (2×20 mL). The combined organic layers were dried (MgSO₄),filtered, evaporated in vacuo and purified by flash chromatography 5:4:1v/v/v DCM/EtOAc/MeOH the resulting purified fractions were combined andevaporated providing 26 mg of the title compound as a white solid (0.052mmol, yield 33%). ¹H-NMR (DMSO-d₆) δ 10.18 (s, 1H), 10.16 to 10.12 (brs, 1H), 8.55 to 8.54 (d, J=5.4 Hz, 1H), 8.35 to 8.31 (t, J=8.3 Hz, 1H),8.30 (s, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 7.91 (s, 1H), 7.39 to 7.36 (m,2H), 7.23 to 7.21 (d, J=10.4 Hz, 1H), 6.63 (s, 1H); MS [M+H]⁺=499.0;LCMS RT=2.85 min.

Intermediate AL Preparation ofN-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Intermediate Z was used toprepare the title compound by substituting Intermediate AJ forIntermediate Y. ¹H-NMR (DMSO-d₆) δ 10.14 (s, 1H), 10.09 to 10.04 (br s,1H), 8.54 to 8.53 (d, J=5.5 Hz, 1H), 8.30 to 8.26 (t, J=8.5 Hz, 1H),8.00 (s, 1H), 7.86 (s, 1H), 7.76 (s, 1H), 7.39 to 7.38 (d, J=5.2 Hz,1H), 7.35 to 7.32 (d, J=12.0 Hz, 1H), 7.21 to 7.18 (d, J=10.2 Hz, 1H),4.28 (s, 2H), 3.22 (s, 3H); MS [M+H]⁺=476.1; LCMS RT=2.77 min.

Intermediate AM Preparation ofN-{4-[4-amino-6-(cyanomethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Intermediate AC was used toprepare the title compound by substituting Intermediate AJ forIntermediate M. ¹H-NMR (Acetone-d₆) δ 10.99 (s, 1H), 9.39 (s, 1H), 8.59to 8.58 (d, J=5.1 Hz, 1H), 8.51 to 8.47 (t, J=8.5 Hz, 1H), 7.84 (s, 1H),7.82 to 7.81 (d, J=6.4 Hz, 1H), 7.75 (s, 1H), 7.38 to 7.35 (m, 2H), 7.30to 7.28 (d, J=8.4 Hz, 1H), 3.86 (s, 2H); MS [M+H]⁺=471.0; LCMS RT=2.75min.

Intermediate AN Preparation of ethyl4-amino-5-{4-[({[6-(trifluoro-methyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate

The procedure used for the preparation of Intermediate W was used toprepare the title compound by substitutingphenyl[6-(trifluoromethyl)pyridin-2-yl]carbamate for phenyl(4-tert-butylpyridin-2-yl)carbamate. ¹H-NMR (DMSO-d₆) δ 9.89 (s, 1H),9.74 (s, 1H), 8.13 (s, 1H), 8.02 to 7.97 (m, 2H), 7.92 (s, 1H), 7.55 (d,J=9 Hz, 2H), 7.53 to 7.50 (m, 1H), 7.35 (d, J=9 Hz, 2H), 5.12 (bs, 1H),4.07 (q, J=7 Hz, 2H), 1.09 (t, J=7 Hz, 3H); MS [M+H]⁺=486.0; LCMSRT=2.92 min; TLC R_(f)=0.38 (3:1 v/v CH₂Cl₂-THF).

Intermediate AO Preparation of4-amino-5-{4-[({[6-(trifluoromethyl)-pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylicacid

The procedure used for the preparation of Intermediate S was used toprepare the title compound by substituting Intermediate AN forIntermediate J. ¹H-NMR (DMSO) δ 10.29 (bs, 1H), 8.03 to 7.96 (m, 3H),7.86 (s, 1H), 7.53 (d, J=8.5 Hz, 2H), 7.45 (d, J=7.0 Hz, 1H), 7.33 (d,J=8.6 Hz, 2H); MS [M+H]⁺=458.1; LCMS RT=2.51 min.

Intermediate AP Preparation of4-amino-N-(2,2,2-trifluoroethyl)-5-{4-[({[6-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)-amino]phenyl}pyrrolo-[2,1-f][1,2,4]triazine-6-carboxamide

The procedure used for the preparation of Intermediate T was used toprepare the title compound by substituting Intermediate AO forIntermediate S. ¹H-NMR (CD₃OD) δ 8.05 (s, 1H), 7.97 (s, 1H), 7.85 (s,1H), 7.67 (d, J=8.7 Hz, 2H), 7.56 (d, J=8.7 Hz, 1H), 7.46 to 7.41 (m,3H), 3.94 (q, J=8.9 Hz, 2H); MS [M+H]⁺=539.0; LCMS RT=2.71.

Intermediate AQN-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[6-(trifluoromethyl)pyridin-2-yl]urea

Step 1: Preparation ofN-{4-[4-amino-6-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[6-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Intermediate Y was used toprepare the title compound by substituting Intermediate AN forIntermediate W. ¹H-NMR (DMSO-d₆) δ 9.87 (s, 1H), 9.71 (s, 1H), 8.03 to7.99 (m, 3H), 7.82 (s, 1H), 7.65 (s, 1H), 7.57 to 7.55 (m, 3H), 7.50 to7.47 (m, 1H), 7.37 (d, J=8.5 Hz, 2H), 4.97 to 4.94 (m, 1H), 4.36 (d,J=5.2 Hz, 2H); MS [M+H]⁺=444.0; LCMS RT=2.24 min.

Step 2: Preparation of Title Compound

The procedure used for the preparation of Intermediate Z was used toprepare the title compound by substitutingN-{4-[4-amino-6-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[6-(trifluoromethyl)pyridin-2-yl]ureafor Intermediate Y. ¹H-NMR (DMSO-d₆) δ 9.90 (s, 1H), 9.74 (s, 1H), 8.05to 7.99 (m, 2H); 7.85 (s, 1H), 7.75 (s, 1H), 7.58 (d, J=8.8, 2H), 7.50(dd, J=8.8, J=6.8, 1.2, 1H), 7.37 (d, J=8.0, 2H), 4.26 (s, 2H), 3.19 (s,3H); MS [M+H]⁺=457.9; LCMS RT=2.70.

Intermediate AR Preparation ofN-{4-[4-amino-6-(methoxymethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-chloro-5-(trifluoromethyl)-phenyl]urea

Step 1: Preparation of ethyl4-amino-5-{4-[({[2-chloro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate

To a solution of DCE (5 mL) was added Intermediate H (300 mg, 1.01 mmol)followed by 2-chloro-1-isocyanato-4-(trifluoromethyl)benzene (0.32 mL,2.12 mmol). The reaction was stirred under N₂ at rt for 1 h, and then aq2 N HCl (0.50 mL, 1.01 mmol) was added to the reaction followed by DMF(5 mL). The solution was heated for an additional 1 h. Upon cooling tort, the solution was diluted with EtOAc, transferred to a separatoryfunnel, and washed with aq saturated NaHCO₃. The aq layer was backextracted with EtOAc. The combined organic layers were collected, dried,concentrated, and purified by column chromatography (95:5 v/vCH₂Cl₂-MeOH). The resulting fractions containing product wereconcentrated and triturated using CH₂Cl₂ and hexanes. The product wasfiltered and dried in vacuo to afford 408 mg of the above compound as awhite solid (0.79 mmol, yield 78%). ¹H-NMR (DMSO-d₆) δ 9.72 (s, 1H),8.67 (s, 1H), 8.64 (s, 1H), 8.13 (s, 1H), 8.08 (br s, 1H), 7.93 (s, 1H),7.72 (d, J=8.5 Hz, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.39 to 7.36 (m, 1H),7.34 (d, J=8.6 Hz, 2H), 5.10 (br s, 1H), 4.09 (q, J=7.0 Hz, 2H), 1.12(t, J=7.1 Hz, 3H); MS [M+H]⁺=519; LCMS RT=3.58 min; TLC R_(f)=0.26 (95:5v/v CH₂Cl₂-MeOH).

Step 2: Preparation ofN-{4-[4-amino-6-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Intermediate Y was used toprepare by substituting ethyl4-amino-5-{4-[({[2-chloro-5-(trifluoromethyl)-phenyl]amino}carbonyl)-amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylatefor Intermediate W.

Step 3: Preparation of Title Compound

The procedure used for the preparation of Intermediate Z was used toprepare the title compound by substitutingN-{4-[4-amino-6-(hydroxymethyl)pyrrolo[2,1-f]-[1,2,4]triazin-5-yl]phenyl}-N′-[2-chloro-5-(trifluoromethyl)-phenyl]ureafor Intermediate Y. ¹H-NMR (DMSO-d₆) δ 8.55 (s, 1H), 7.84 (s, 1H), 7.74(s, 1H); 7.68 to 7.62 (m, 3H), 7.33 to 7.28 (m, 3H), 4.26 (s, 2H), 3.19(s, 3H); MS [M+H]⁺=491.1; LCMS RT=3.25.

Intermediate AS Preparation ofN-{4-[4-amino-6-(cyanomethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea

Step 1: Preparation of ethyl4-amino-5-{4-[({[2-chloro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]-3-fluorophenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate

The procedure used for the preparation of Intermediate AR, step 1 wasused to prepare ethyl4-amino-5-{4-[({[2-chloro-5-(trifluoromethyl)phenyl]amino}-carbonyl)-amino]-3-fluorophenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylateby substituting Intermediate I for Intermediate H. ¹H-NMR (CD₃OD) δ 9.46(s, 1H), 8.91 (d, J=4.8 Hz, 1H), 8.65 (d, J=2.4 Hz, 1H), 8.31-8.27 (m,2H), 8.01 (s, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.35-7.23 (m, 3H), 4.18 (q,J=8.0 Hz, 2H), 1.20 (t, J=8.0 Hz, 3H); MS [M+H]⁺=537.2; LCMS RT=3.76.

Step 2: Preparation ofN-{4-[4-amino-6-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Intermediate AR, step 2 wasused to prepare the intermediate methyl alcohol derivative bysubstituting ethyl4-amino-5-{4-[({[2-chloro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]-3-fluorophenyl}-pyrrolo-[2,1-f][1,2,4]triazine-6-carboxylatefor ethyl4-amino-5-{4-[({[2-chloro-5-(trifluoro-methyl)-phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]-triazine-carboxylate.¹H-NMR (CD₃OD) δ 8.65 (d, J=2.4 Hz, 1H), 8.31 (t, J=8.4 Hz, 1H), 7.89(s, 1H), 7.82 (s, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.38-7.28 (m, 3H), 4.54(s, 2H); MS [M+H]⁺=495.2; LCMS RT=3.08.

Step 3: Preparation of Title Compound

The procedure used for the preparation of Intermediate AC was used toprepare the title compound by substitutingN-{4-[4-amino-6-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]ureafor Intermediate M. ¹H-NMR (CD₃OD) δ 9.48 (s, 1H), 8.92 (s, 1H), 8.66(s, 1H), 8.40-8.35 (m, 1H), 7.94 (s, 1H), 7.89 (s, 1H), 7.64 (d, J=9.2Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 7.34-7.32 (m, 1H), 7.29-7.26 (m, 1H),3.82 (s, 2H); MS [M+H]⁺=504; LCMS RT=3.10.

Intermediate AT Preparation of4-amino-7-bromo-5-{4-[({[2-fluoro-5-(trifluoromethyl)-phenyl]amino}carbonyl)amino]phenyl}-N-(2,2,2-trifluoroethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide

To a suspension of Intermediate T(4-amino-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-N-(2,2,2-trifluoroethyl)-pyrrolo-[2,1-f][1,2,4]triazine-6-carboxamide(505 mg, 0.9 mmol)) in acetonitrile (20 ml) was added N-bromosuccinimide(177 mg, 1.0 mmol) and the reaction mixture was heated at 60° C. in asealed vial for 1 h. After cooling to 0° C., the crude was filtered andwashed with cold CH₃CN (3×) and subsequently ethyl ether to afford 550mg as solid. No further purification was needed. MS [M+H]⁺=634.1; LCMSRT=3.12 min.

Intermediate AU Preparation of4-amino-5-4-[([2-fluoro-5-(trifluoromethyl)-phenyl]aminocarbonyl)amino]phenyl-7-formyl-N-(2,2,2-trifluoroethyl)pyrrolo-[2,1-f][1,2,4]triazine-6-carboxamide

To a solution Intermediate AT((4-amino-7-bromo-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-N-(2,2,2-trifluoro-ethyl)-pyrrolo-[2,1-f][1,2,4]triazine-6-carboxamide(400 mg, 0.63 mmol)) in THF (10 ml) at −78° C. under N₂ was added n-BuLi(1.26 ml, 3.15 mmol) slowly. After 15 min., DMF was added and thereaction mixture was allowed to warm up to rt. The reaction was dilutedwith EtOAc and was washed with H₂O (3×). The organic layer was dried(Na₂SO₄), concentrated and purified via flash column chromatography(95:5 v/v CH₂Cl₂-MeOH) to afford 230 mg of the title compound (yield62%). ¹H-NMR (DMSO-d₆) δ10.36 (s, 1H), 9.33 (s, 1H), 9.05 (dd, J=6 Hz,1H), 9.93 (d, J=3 Hz, 1H), 8.63 to 8.59 (m, 1H), 8.21 (s, 1H), 7.93 (s,3H), 7.55 to 7.32 (m, 6H), 3.98 to 3.92 (m, 2H); MS [M+H]⁺=584.0; LCMSRT=3.21 min.

Intermediate AV Preparation ofN-{4-[4-amino-7-bromo-6-(methoxymethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

To a suspension of Intermediate AA(N-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoro-methyl)phenyl]urea(750 mg, 1.58 mmol)) in acetonitrile (7 ml) was added N-bromosuccinimide(365 mg, 2.0 mmol) and the mixture was heated at 60 C in a sealed vialfor 1 h. After cooling to 0° C., the reaction was filtered and washedwith cold CH₃CN and ethyl ether (3×) to give the crude product as asolid, which was purified via flash column chromatography (95:5 v/vCH₂Cl₂-MeOH) to afford additional 50 mg of the title compound. ¹H-NMR(DMSO-d₆) δ 9.34 (s, 1H), 8.95 (d, J=3 Hz, 1H), 8.6 (m, 1H), 7.98 (s,1H), 7.60 (d, J=3 Hz, 1H), 7.57 to 7.58 (m, 1H), 7.49 (m, 1H), 7.38 to7.34 (m, 2H), 4.21 (s, 2H), 3.16 (s, 3H); MS [M+H]⁺=553; LCMS RT=3.24min.

Intermediate AW Preparation ofN-{4-[4-amino-7-formyl-6-(methoxymethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

The procedure used for the preparation of Intermediate AU was used toprepare the title compound by substituting Intermediate AV(N-{4-[4-amino-7-bromo-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoro-methyl)phenyl]urea)for Intermediate AT(4-amino-7-bromo-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-N-(2,2,2-trifluoroethyl)-pyrrolo-[2,1-f][1,2,4]triazine-6-carboxamide).The title compound was obtained as isolated and was used without furtherpurification. MS [M+H]⁺=503; LCMS RT=3.21 min.

Intermediate AX Preparation of1-[4-amino-5-(4-amino-3-fluorophenyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]ethanone

Step 1: Preparation of 1H-pyrrole-2,4-dicarbonitrile

To a solution of ACN (15 mL) was added pyrrole (1.03 mL, 14.9 mmol)which was cooled in an ice/salt bath. Chlorosulfonyl isocyanate (2.73mL, 31.3 mmol) was diluted in ACN (5 mL) and then added to the reactiondropwise over the following 30 min. The ice/salt bath was removed andthe solution was allowed to warm to rt over the next 1.5 h. The solutionwas then cooled in an ice/salt bath and DMF (5.00 mL, 65.0 mmol) wasslowly added via an addition funnel. The solution was allowed to slowlywarm to rt over 17 h. The solution was cooled in an ice/salt bath and aq1 N NaOH (50 mL) was added followed by EtOAc (50 mL). The solution wastransferred to a separatory funnel, and the organic layer was isolatedand the aqueous layer was back extracted with EtOAc (2×). The collectedorganic was washed with aq saturated NaHCO₃ followed by H₂O (100 mL).The aqueous layers were back extracted with EtOAc (2×50 mL). Thecombined organic layers were collected, dried (MgSO₄), concentrated ontosilica gel, and purified by column chromatography (9:1 v/v CH₂Cl₂-EtOAc)to afford 1.28 g of the above compound as a white solid (10.9 mmol,yield 73%). ¹H-NMR (DMSO-d₆) δ 13.29 (br s, 1H), 8.00 (s, 1H), 7.49 (s,1H); LCMS RT=1.65 min.

Step 2: Preparation of 1-amino-1H-pyrrole-2,4-dicarbonitrile

To a solution of DMF (100 mL) was added 1H-pyrrole-2,4-dicarbonitrile(1.00 g, 8.54 mmol) followed by NaH, 60% dispersion in mineral oil (0.51g, 12.8 mmol). The solution was stirred at rt for 15 min and then(aminooxy)(diphenyl)phosphine oxide (2.99 g, 12.8 mmol) was added, andthe solution was heated to 80° C. for 2 h. Upon cooling to rt thesolution was filtered washing with CH₂Cl₂. The solution was partiallyconcentrated and a white precipitate formed which was filtered. Themother liquor was then evaporated under vacuum and subsequently purifiedby MPLC (Isco) 100% CH₂Cl₂ ramping to 9:1 v/v CH₂Cl₂-EtOAc. Theresulting purified fractions were combined and concentrated in vacuoyielding 0.92 g of a white solid (6.98 mmol, yield 82%). ¹H-NMR(DMSO-d₆) (17.92 (d, J=1.8 Hz, 1H), 7.39 (d, J=1.9 Hz, 1H), 6.66 (s,2H); MS [M+H]⁺=133.0; LCMS RT=0.96 min.

Step 3: Preparation of4-aminopyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile

To a solution of EtOH (50 mL) was added1-amino-1H-pyrrole-2,4-dicarbonitrile (1.00 g, 7.57 mmol) followed byformamidine acetate (9.46 g, 90.8 mmol) and potassium carbonate (14.6 g,106.0 mmol). The solution was heated to 80° C. for 2 h. Upon cooling tort, the reaction mixture was diluted with EtOAc transferred to aseparatory funnel and washed with water. The organic layer wascollected, dried (MgSO₄), filtered, and concentrated to dryness. Thecrude material was then triturated with EtOH-water. The solid wascollected, washed with water, and dried under vacuum to afford 0.91 g ofthe above compound as a yellow-orange solid (5.70 mmol, yield 75%).¹H-NMR (DMSO-d₆) δ 8.37 (d, J=1.8 Hz, 1H), 8.19 (d, J=17.4, 2H), 7.93(s, 1H), 7.27 (d, J=1.8 Hz, 1H); LCMS RT=1.14 min.

Step 4: Preparation of4-aminopyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde

To a solution of THF (200 mL) was added4-aminopyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (1.00 g, 6.28 mmol).The solution was heated until all starting material was in solution andwas then cooled in an ice-water bath. 1 M Diisobutylaluminum hydride inTHF (50.3 mL, 50.3 mmol) was then added to the solution which wasstirred for 1 h. EtOAc was added to the solution and it was then allowedto warm to rt. Wet silica gel was carefully pipetted into the solution,and the reaction mixture was heated to 50° C. for 30 min, filteredthrough Celite, and washed with excess EtOAc. The solution wastransferred to a separatory funnel and washed with water. The organiclayer was collected, dried (MgSO₄), filtered, and concentrated todryness yielding 0.92 g of yellow solid (5.69 mmol, yield 91%). ¹H-NMR(DMSO-d₆) δ 9.91 (s, 1H) 7.92 (d, J=1.7 Hz, 1H), 8.14 (d, J=35.3 Hz,2H), 7.89 (s, 1H), 7.30 (d, J=1.8 Hz, 1H); MS [M+H]⁺=163.3; LCMS RT=1.07min.

Step 5: Preparation of1-(4-aminopyrrolo[2,1-f][1,2,4]triazin-6-yl)ethanol

To a solution of THF (100 mL) was added 3.0 M methylmagnesium bromide indiethyl ether (14.0 mL, 41.9, mmol) cooled in an ice bath. Then4-aminopyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde (0.68 g, 4.19 mmol)was added as a solution in THF (200 mL) via an addition funnel. Thereaction was allowed to slowly warm to rt over the following 17 h. Thereaction was carefully treated with MeOH (10 mL) followed by aqsaturated NH₄Cl (50 mL) and EtOAc (50 mL). The solution was transferredto a separatory funnel and the organic layer was isolated while theaqueous layer was back extracted with EtOAc (4×20 mL). The combinedorganic layers were collected, dried (MgSO₄), filtered, and concentratedto dryness. The crude material was then purified by flash chromatography(85:15 v/v CH₂Cl₂-MeOH). The purified fractions were concentrated invacuo and then dried under vacuum to afford 422 mg of the above compound(2.37 mmol, yield 56%). ¹H-NMR (DMSO-d₆) δ 7.72 (s, 1H), 7.59 (br s,2H), 7.45 (dd, J=0.5 Hz, 1.7 Hz, 1H), 6.76 (dd, J=0.5 Hz, 1.7 Hz, 1H),5.03 (d, J=4.7 Hz, 1H), 4.79 (m, 1H), 1.38 (d, J=6.5 Hz, 3H); MS[M+H]⁺=179.3; LCMS RT=1.04 min.

Step 6: Preparation of1-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]ethanol

To a solution of AcOH (70 mL) was added1-(4-aminopyrrolo[2,1-f][1,2,4]triazin-6-yl)ethanol (611 mg, 3.43 mmol)followed by the addition of a 0.5 M solution of 37% formaldehyde inwater (0.26 mL, 3.43 mmol) and morpholine (0.30 mL, 3.43 mmol) in AcOH(6.86 mL) was added. The reaction was heated to 60° C. for 1.5 h. Thesolution was allowed to cool to rt and was then evaporated via rotaryevaporation chasing the remaining AcOH with toluene. The crude materialwas purified by column chromatography (85:15 v/v CH₂Cl₂-EtOAc) to afford633 mg of the above compound (2.28 mmol, yield 67%). ¹H-NMR (DMSO-d₆) δ7.79 (s, 1H), 7.57 (br s, 2H), 6.85 (s, 1H), 4.94 (m, 1H), 3.84 (m, 2H),3.49 (m, 4H), 2.37 (m, 4H), 1.41 (d, J=6.6 Hz, 3H); MS [M+H]⁺=278.0;LCMS RT=1.01 min.

Step 7: Preparation of ethyl1-[4-amino-5-bromo-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-6-yl]ethanol

To a solution of THF (500 mL) was added1-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]ethanol(2.49 g, 8.99 mmol), which was cooled in an ACN-dry ice bath. Then1,3-dibromo-5,5-dimethylhydantoin (1.29 g, 4.50 mmol) was added and intwo batches 20 min apart and the reaction stirred for a total of 45 min.The reaction was quenched with aq saturated Na₂SO₃ (500 mL) as thesolution warmed to rt. EtOAc (500 mL) was added to the reaction and thesolution was transferred to a separatory funnel and the organic layerwas isolated while the aqueous layer was back extracted with EtOAc(2×200 mL). The combined organic layers were collected, dried (MgSO₄),filtered, and concentrated to dryness. The crude material was purifiedby MPLC (Isco) 100% CH₂Cl₂ to 9:1 v/v CH₂Cl₂-MeOH. The resultingpurified fractions were combined and concentrated in vacuo yielding 2.52g of the above compound (7.09 mmol, yield 79%). ¹H-NMR (DMSO-d₆) δ 7.85(s, 1H), 5.85 (d, J=5.3, 1H), 4.91 (m, 1H), 4.01 (d, J=13.6 Hz, 1H),3.87 (d, J=13.2 Hz, 1H), 3.50 (m, 2H), 2.50 (m, 4H), 2.39 (m, 4H), 1.45(d, J=6.5 Hz, 3H); MS [M+H]⁺=355.9; LCMS RT=1.08 min.

Step 8: Preparation of1-[4-amino-5-bromo-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-6-yl]ethanone

To a solution of THF (100 mL) was added ethyl1-[4-amino-5-bromo-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]ethanol(419 mg, 1.18 mmol) followed by Dess-Martin periodinane (748 mg, 1.76mmol). The solution was stirred at rt for 1 h and then quenched byaddition of aqueous saturated sodium thiosulfate and NaHCO₃ (100 mL)followed by EtOAc (100 mL) to the reaction. The solution was stirred for30 min at rt and then transferred to a separatory funnel. The organiclayer was isolated while the aqueous layers were back extracted withEtOAc (2×50 mL). The combined organic layers were collected, dried(MgSO₄), filtered, and concentrated to dryness. The crude material wasthen triturated with THF-Et₂O. The solid was collected, washed with Et₂O(150 mL), and dried under vacuum. The mother liquor was concentrated andpurified by MPLC (Isco) 100% CH₂Cl₂ to 9:1 v/v CH₂Cl₂-MeOH. Theresulting purified fractions were combined with the solid andconcentrated in vacuo yielding 344 mg of the above compound (0.97 mmol,yield 83%). ¹H-NMR (DMSO-d₆) δ 8.35 (br s, 1H), 7.94 (s, 1H), 7.13 (brs, 1H), 4.02 (s, 2H), 3.47 (m, 4H), 2.64 (s, 3H), 2.35 (m, 4H); MS[M+H]⁺=354.0; LCMS RT=1.11 min.

Step 9: Preparation of tert-butyl{4-[6-acetyl-4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}carbamate

To a solution of 1,4-dioxane (30 mL) was added1-[4-amino-5-bromo-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]ethanone(222 mg, 0.627 mmol),tert-butyl[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate(423 mg, 1.25 mmol), and Na₂CO₃ (199 mg, 1.88 mmol). N₂ was bubbledthrough the solution for 15 min, and thentetrakis(triphenylphosphine)palladium(0) and water (3.0 mL) were added.N₂ was again bubbled through the solution for 15 min, and then thesolution was heated to 80° C. for 17 h. Upon cooling to rt EtOAc (50 mL)and water (50 mL) were added to the reaction mixture which was thentransferred to a separatory funnel. The organic layer was isolated whilethe aqueous layer was back extracted with EtOAc (2×50 mL). The combinedorganic layers were collected, dried (MgSO₄), filtered, and concentratedto dryness. The crude material was then purified by columnchromatography (5:4:1 v/v/v CH₂Cl₂-EtOAc-MeOH. The resulting purifiedfractions were combined and concentrated in vacuo yielding 305 mg of theabove compound as a white solid (0.63 mmol, yield 100%). ¹H-NMR(DMSO-d₆) δ 9.16 (s, 1H), 7.97 (s, 1H), 7.78 (t, J=8.4 Hz, 1H), 7.28(dd, J=1.7 Hz, 11.1 Hz, 1H), 7.15 (dd, J=2.0 Hz, 8.4 Hz, 1H), 4.06 (s,2H), 3.49 (m, 4H), 2.42 (m, 4H), 2.15 (s, 3H), 1.49 (s, 9H); MS[M+H]⁺=485.1; LCMS RT=2.28 min.

Step 10: Preparation of the Title Compound

To a solution of CH₂Cl₂ (50 mL) was added of tert-butyl{4-[6-acetyl-4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2fluorophenyl}-carbamate (291 mg, 0.60 mmol) followed by trifluoroaceticacid (5 mL). The solution was allowed to stir for 30 min at rt. Aqsaturated NaHCO₃ was added to the solution until bubbling stopped.Additionally CH₂Cl₂ was added and the solution was then transferred to aseparatory funnel. The organic layer was isolated while the aqueouslayer was back extracted with CH₂Cl₂ (2×25 mL). The combined organiclayers were collected, dried (MgSO₄), filtered, and concentrated todryness yielding 214 mg of the above compound as a white solid (0.56mmol, yield 93%). ¹H-NMR (DMSO-d₆) δ 7.95 (s, 1H), 7.08 (dd, J=1.7 Hz,10.3 Hz, 1H), 6.92 (dd, J=1.8 Hz, 7.9 Hz, 1H), 6.86 (t, J=8.7 Hz, 1H),5.47 (s, 2H), 4.05 (s, 2H), 3.49 (m, 4H), 2.41 (m, 4H), 2.06 (s, 3H); MS[M+H]⁺=385.1; LCMS RT=1.16 min.

Intermediate AY Preparation of Ethyl4-amino-7-bromo-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f]-[1,2,4]triazine-6-carboxylate

Step 1: Preparation of Ethyl4-amino-7-bromo-5-(4-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate

Ethyl4-amino-5-(4-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate(2.0 g, 6.11 mmol) was suspended in ACN and treated withN-bromosuccinimide (1.20 g, 6.72 mmol). The dark suspension was heatedto 60° C. for 1 h. The suspension was cooled and filtered. The brownsolid was washed with ACN and MeOH. The product was collected byfiltration to give 2.06 g of a yellow brown solid (83%). ¹H-NMR(DMSO-d₆) δ 8.26 (d, J=8.8, 2H), 8.07 (s, 1H), 7.64 (d, J=8.8, 2H), 4.02(q, J=7.0, 2H), 0.95 (t, J=7.0, 3H); MS [M+H]⁺=406.1, 408.0; LCMSRT=2.93.

Step 2: Preparation of Ethyl4-amino-5-(4-aminophenyl)-7-bromopyrrolo[2,1-f][1,2,4]triazine-6-carboxylate

Ethyl-4-amino-7-bromo-5-(4-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate(2.06 g, 5.07 mmol) was suspended in EtOH (30 mL) and treated withtin(II)chloride dihydrate (3.66 g. 16.2 mmol). The mixture was heated toreflux for 18 h. The mixture was concentrated then diluted with EtOAcand saturated NaHCO₃ solution. The emulsion was filtered and thefiltrate was transferred to a separatory funnel. The organic layer waswashed with water and saturated NaCl solution, dried then (MgSO₄) andconcentrated to afford 1.5 g of the desired product as tan solid (79%).¹H-NMR (DMSO-d₆) δ 8.00 (s, 1H), 7.00 (d, J=8.6, 1H), 6.62 (d, J=9.2,3H), 5.40 (bd, 2H), 5.19 (bs, 2H), 4.05 (q, J=7.0, 2H), 1.03 (t, J=7.0,3H); MS [M+H]⁺=376.0, 378.0; LCMS RT=2.02.

Step 3. Preparation of Title Compound

Ethyl-4-amino-5-(4-aminophenyl)-7-bromopyrrolo[2,1-f][1,2,4]triazine-6-carboxylate(1.5 g, 3.99 mmol) was suspended in THF (20 mL) and treated withtriethylamine (0.56 mL, 3.99 mmol) andphenyl[4-(trifluoromethyl)pyridin-2-yl]carbamate (1.13 g, 3.99 mmol).The mixture was heated to 70° C. for 18 h. After cooling to rt, hemixture was concentrated then suspended in EtOAc. The product wascollected by filtration to give 2.0 g of a tan solid (89%). ¹H-NMR(DMSO-d₆) δ 9.91 (s, 1H) 9.75 (s, 1H), 8.53 (d, J=5.4, 1H), 8.06 (s,1H), 8.04 (s, 1H), 7.60 (d, J=11, 2H), 7.37-7.31 (m, 3H), 5.15 (bs, 2H),4.04 (q, J=7.1, 2H), 0.99 (t, J=7.2, 3H); MS [M+H]⁺=563.9, 565.9; LCMSRT=3.22.

Intermediate AZ Preparation of ethyl4-amino-7-bromo-5-{-4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate

The procedure used for the preparation of Intermediate AT was used toprepare the title compound by substituting Intermediate W forIntermediate T.

Intermediate AAA5-bromo-6-(methoxymethyl)-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-amine

Step 1: Preparation of(4-aminopyrrolo[2,1-f][1,2,4]triazin-6-yl)methanol

To a solution of THF (150 mL) was added ethyl4-aminopyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (2.29 g, 4.65 mmol)followed by 1 M DIBAL in THF (28.8 mL, 28.8 mmol). The solution wasstirred at rt for 1 h. The rxn mixture was treated with EtOAc followedby aq Rochelle's salt. This heterogeneous mixture was then heated at 60°C. for 30 min. The solution was transferred to a separatory funnel,separated and washed with water. The aq layer was back extracted withEtOAc. The organic layer was dried (MgSO₄), filtered, and concentratedto yield 550 mg (93%) of the desired product. MS [M+H]⁺=165; LCMSRT=1.03.

Step 2: Preparation of[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methanol

To a solution of DMF (50 mL) was added(4-aminopyrrolo[2,1-f][1,2,4]triazin-6-yl)methanol (550 mg, 3.35 mmol)and 4-methylenemorpholin-4-ium chloride (Eur. J. Med. Chem. 1989, 24,379-384) (636 mg, 4.69 mmol). The solution was stirred at rt for 1 h andthen the solvent was evaporated. The oil was triturated with CH₂Cl₂ anda white solid was collected. The free based was obtained by stirringover a Dowex 66 solid support resin in MeOH. The material was filteredand evaporated yielding 794 mg (90%) of the desired product as a whitesolid. MS [M+H]⁺=264; LCMS RT=1.07.

Step 3: Preparation of6-(methoxymethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

The procedure used for the preparation of Intermediate Z was used toprepare the title compound by substituting[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1f][1,2,4]triazin-6-yl]methanolfor Intermediate Y(N-{4-[4-amino-6-(hydroxyl-methyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)-pyridin-2-yl]urea.MS [M+H]⁺=278; LCMS RT=1.07.

Step 4. Preparation of Title Compound

The procedure used for the preparation of the product of step 7 inIntermediate AX (ethyl1-[4-amino-5-bromo-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-6-yl]-ethanol)was used to prepare the title compound by substituting6-(methoxymethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminefor1-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]ethanol.MS [M+H]⁺=356; LCMS RT=1.12.

Intermediate AAB Preparation of1-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Step 1: Preparation of2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

Potassium acetate (3 eq) and4,4,4′,4′5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (1.1 eq) wereadded as solids to a flask then placed under N₂.4-Bromo-2-5-difluoroaniline (1 eq) in DMSO (0.4 M) was then added to theflask. The reaction was taken through three purge-fill cycles using highvacuum then nitrogen and Pd(dppf)CH₂Cl₂ (0.01 eq) was added. Thereaction was again placed under vacuum then blanketed with nitrogen. Thereaction was heated at 80° C. until the TLC showed the completeconsumption of starting bromide (approximately 90 minutes). Aftercooling to rt, EtOAc was added and the reaction was partitioned betweenEtOAc and saturated aqueous bicarbonate. The organic layer was washedwith brine seven times to remove DMSO. The material was then dried(Na₂SO₄) and concentrated under vacuum. The desired product was obtainedafter column chromatography (0-100% v/v CH₂Cl₂/Hexanes). ¹H-NMR(DMSO-d₆) ¹H-NMR (DMSO-d₆) δ 7.03 (dd, J=11.7 Hz, 5.4 Hz, 1H), 6.38 (dd,10.8 Hz, 3.9 Hz, 1H), 5.91 (s 2H) 1.22 (s, 12H); MS [M+H]⁺=256.3, LCMSRT=3.13 min.

Step 2: Preparation of the Title Compound

To a solution of2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1eq) in THF (1 M) was added 2-fluoro-5-trifluoromethyl phenylisocyante(1.2 eq). The reaction was stirred at room temperature overnight. Thedesire product was precipitated from the reaction mixture by theaddition of 1:2 ether/hexanes. The desired title compound was obtainedas a solid after filtration and drying in vacuo. MS [M+H]⁺=461.2, LCMSRT=4.38 min.

Intermediate AAC1-{4-[4-amino-7-formyl-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Step 1: Preparation of1-{4-[4-amino-7-bromo-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a solution of THF (500 mL) was added1-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea(2.29 g, 4.65 mmol). The solution was cooled to −40° C. and then1,3-dibromo-5,5-dimethylhydantoin (665 mg, 2.33 mmol) was added in twobatches 20 min apart. The reaction was stirred at −40° C. for 1 h andthen allowed to warm to rt over the following 2 h. Aq saturated Na₂SO₃was added to the reaction followed by EtOAc. The layers were separatedand the aqueous layer was back extracted with EtOAc. The organic layerwas washed with 1 N NaOH and water, dried (Na₂SO₄), filtered andevaporated to yield 2.83 g crude (107%) of the desired product. MS[M+H]⁺=571; LCMS RT=3.54.

Step 2. Preparation of Title Compound

To a solution of THF (35 mL) was added1-{4-[4-amino-7-bromo-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea(200 mg, 0.35 mmol). The solution was cooled to −77° C., and then 2.5 Mn-BuLi in hexanes (0.70 mL, 1.75 mmol) was added. The reaction wasstirred for 1 min and then DMF (0.16 mL, 2.1 mmol) was added. Thesolution was stirred for an additional 5 min, and the ice bath wasremoved. The reaction was allowed to warm to rt over the following 1 h.EtOAc was added to the solution followed by water. The solution wasseparated and the aqueous layer was back extracted with EtOAc. Thecombined organic fractions were dried (MgSO₄), filtered, and evaporatedyielding the title compound as crude material (216 mg, 119%). MS[M+H]⁺=521; LCMS RT=3.49.

Intermediate AAD5-bromo-6-chloro-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

Step 1: Preparation of2,2,2-trichloro-1-(4-chloro-1H-pyrrol-2-yl)ethanone

To a solution of 2-(trichloroacetyl)pyrrole (4.0 g, 18.83 mmol) inchloroform (28 ml) at 0° C. was added sulfuryl chloride (13 mL, 13.2mmol). The mixture was stirred for 17 hours at room temperature. TLCanalysis indicated 50% conversion of starting material. Sulfurylchloride (13 mL, 13.2 mmol) was added and the reaction mixture wasstirred for another 4 hours at room temperature. The reaction wasquenched with distilled water (50 mL). CH₂Cl₂ (50 mL) was added to thereaction and the solution was transferred to a separatory funnel and theorganic layer was isolated while the aqueous layer was back extractedwith CH₂Cl₂ (2×50 mL). The combined organic layers were collected, dried(MgSO₄), filtered, and concentrated in vacuo to yield 3.5 g of the abovecompound (14.18 mmol, yield 75%). ¹H-NMR (CDCl₃-d₁) δ 9.45 (s, 1H), 7.27(dd, J=2.8, 1.6, 1H), 7.12 (dd, J=3.2, 1.6 Hz, 1H).

Step 2. Preparation of 4-chloro-1H-pyrrole-2-carboxamide

A solution of 2,2,2-trichloro-1-(4-chloro-1H-Pyrrol-2-yl)ethanone (14.0g, 56.7 mmol) in THF (100 mL) was bubbled with ammonium gas for 2 h atroom temperature. TLC analysis indicated that there was completeconversion of starting material. The reaction mixture was concentratedin vacuo to yield 7.5 g of the above compound (51.88 mmol, yield 92%).¹H-NMR (Acetone-d₆) δ 10.92 (br s, 1H), 7.21 (br s, 1H), 7.02 (s, 1H),6.84 (s, 1H), 6.57 (br s, 1H).

Step 3. Preparation of 4-chloro-1H-pyrrole-2-carbonitrile

To a solution of 4-chloro-1H-pyrrole-2-carboxamide (7.5 g, 51.88 mmol)in toluene (50 mL) was added POCl₃ (5.8 mL, 62.26 mmol). The mixture washeated to 80° C. for 4 hours. TLC analysis indicated that there wascomplete conversion of starting material. Toluene and excess POCl₃ wereremoved under reduced pressure and the remaining solids were dissolvedin EtOAc (30 mL). The pH was adjusted to 8 using 1 N NaOH and thesolution was transferred to a separatory funnel and the organic layerwas isolated while the aqueous layer was back extracted with EtOAc,(2×50 mL). The combined organic layers were collected, dried (MgSO₄),filtered, and concentrated in vacuo. The crude material was purified bycolumn chromatography (60% EtOAc/Hexanes) to afford 3.6 g of the abovecompound (28.45 mmol, yield 55%). ¹H-NMR (Acetone-d₆) δ 11.62 (br s,1H), 7.25 (dd, J=2.8, 1.2 Hz, 1H), 6.93 (dd, J=2.8, 1.2 Hz, 1H).

Step 4. Preparation of 1-amino-4-chloro-1H-pyrrole-2-carbonitrile

To a rapidly stirred solution of 4-chloro-1H-pyrrole-2-carbonitrile (3.6g, 28.4 mmol) in DMF (75 mL) was added NaH (1.7 g, 42.7 mmol) portionwise over 20 min. The dark brown solution was allowed to stir for anadditional 10 min. The aminating reagent ((aminooxy)(diphenyl)phosphineoxide) (10 g, 42.7 mmol) was added in one portion. The mixture washeated to 80° C. for 6 hours. The reaction was quenched with distilledwater (100 mL). EtOAc (50 mL) was added to the reaction and the solutionwas transferred to a separatory funnel and the organic layer wasisolated while the aqueous layer was back extracted with EtOAc (2×50mL). The combined organic layers were collected, dried (MgSO₄),filtered, and concentrated in vacuo to yield 3.4 g of the above compound(24.02 mmol, yield 84%).

Step 5. Preparation of 6-chloropyrrolo[2,1-f][1,2,4]triazin-4-amine

To a stirred suspension of 1-amino-4-chloro-1H-pyrrole-2-carbonitrile(3.4 g, 24.02 mmol) in EtOH (160 mL) was added formamidinium acetate (25g, 240.2 mmol). The mixture was heated to 80° C. over night. TLCanalysis indicated that there was complete conversion of startingmaterial. The reaction mixture was cooled to room temperature and thenfiltered. Ethanol was removed under reduced pressure and the remainingsolids were purified by column chromatography (EtOAc) to afford 2.2 g ofthe above compound (13.1 mmol, yield 54%). ¹H-NMR (MeOD-d₄) δ 7.77 (s,1H), 7.56 (d, J=1.6 Hz, 1H), 6.82 (d, J=1.6 Hz, 1H); LCMS RT=1.30 min;MS {M+H]⁺=168.8

Step 6. Preparation of6-chloro-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

To a solution of AcOH (30 mL) was added formaldehyde (1.2 g, 14.95mmol). The reaction mixture was allowed to stir for 20 minutes at roomtemperature. 6-chloropyrrolo[2,1-f][1,2,4]triazin-4-amine (2.1 g, 12.46mmol) was introduced and the reaction mixture was heated to 80° C. overnight. TLC analysis indicated that there was complete conversion ofstarting material. The solution was allowed to cool to rt and was thenneutralized by 1 N NaOH. EtOAc (30 mL) was added to the reaction and thesolution was transferred to a reparatory funnel and the organic layerwas isolated while the aqueous layer was back extracted with EtOAc (2×50mL). The combined organic layers were collected, dried (MgSO₄),filtered, and concentrated in vacuo to yield 3.0 g of the above compound(11.2 mmol, yield 90%). ¹H-NMR (MeOD-d₄) δ 8.05 (s, 1H), 7.13 (s, 1H),4.75 (s, 2H), 3.90 (br s, 4H), 3.42 (br s, 4H); MS [M+H]⁺=267.8; LCMSRT=1.08 min.

Step 7. Preparation of Title Compound

To a solution of6-chloro-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(0.9 g, 3.36 mmol) in DMF (5 mL) at −20° C. was added1,3-dibromo-5,5-dimethylhydantoin (0.43 g, 1.51 mmol) portion wise over30 min. The reaction mixture was stirred for 20 minutes at thattemperature. TLC analysis indicated that there was complete conversionof starting material. The reaction was quenched with distilled water (30mL) as the solution warmed to rt. CH₂Cl₂ (30 mL) was added to thereaction and the solution was transferred to a separatory funnel and theorganic layer was isolated while the aqueous layer was back extractedwith CH₂Cl₂ (4×20 mL). The combined organic layers were collected, dried(MgSO₄), filtered, and concentrated to dryness. The crude material waswashed with diethyl ether (10 mL). The white precipitate was collectedand dried under vacuum to yield 0.6 g of the above compound (1.73 mmol,yield 51%). ¹H-NMR (CD₃OD-d₄) δ 7.94 (s, 1H), 3.79 (s, 2H), 3.05 (t,J=4.8 Hz, 4H), 2.39 (t, J=4.8 Hz, 4H); MS [M+H]⁺=347.7; LCMS RT=1.21min.

Intermediate AAE Preparation of6-Bromopyrrolo[2,1-f][1,2,4]triazin-4-amine

Step 1: Preparation of Pyrrol-1-yl-carbamic acid tert-butyl ester

A flask (fitted with a Dean-Stark trap) containing a stirred solution oftert-butylcarbazate (100, 0.757 mol), 2,5-dimethoxytetrahydrofuran (108g, 0.832 mol) and 2 N HCl (10 mL) in 1,4-dioxane (700 mL) was heatedunder nitrogen at 90° C. As the reaction progressed over several hours,the solution changed from pale yellow to orange and began to reflux. Thereaction was monitored by the amount of distillate collected in the D/Strap (primarily CH₃OH, 2 moles/1 mole reagent). As methanol collectionapproached the theoretical amount (50 mL) a sample was analyzed by TLC(silica gel, 1:3 EtOAc/hexane, ninhydrin stain) to confirm reactioncompletion. Heating was shut off and the reaction was allowed to coolsomewhat before adding saturated sodium bicarbonate solution (˜25 mL) toneutralize the hydrochloric acid. The quenched mixture was filteredthrough a sintered-glass funnel and concentrated in vacuo to leave anorange, semi-solid residue. The residue was suspended in diethyl ether(minimum volume) and the nearly colorless solids were collected bysuction filtration, washed with hexane and air-dried to afford 60.2 g(40%) of product. A second crop (yellow-tan solids) from the motherliquors was isolated: 29.0 g, (19%). Additional material which waspresent in the mother liquors could be recovered by silica gelchromatography to increase the yield. ¹H-NMR (CD₃OD): δ 10.23 (br s,1H), 6.66 (t, 2H, J=2.2 Hz), 5.94 (t, 2H, J=2.2), 1.42 (s, 9H); MS:GC/MS (+esi): m/z=182.9 [MH]⁺

Step 2: Preparation of (2-Cyano-pyrrol-1-yl)-carbamic acid, tert-butylester

A 2 L, 3-neck RB was fitted w/stir bar, N₂ inlet, rubber septumlow-temp. thermometer and ice/acetone cooling bath. Pyrrol-1-yl-carbamicacid tert-butyl ester (99.0 g, 0.543 mol) was added to the reactor,dissolved w/anhydrous acetonitrile (700 mL) and the stirred solution wascooled to 0° C. Chlorosulfonyl isocyanate (49.7 mL, 0.57 mol) was addeddropwise via syringe (maintaining an internal temp. below 5° C.); after˜20 minutes a suspension was observed. After 45 minutesN,N-dimethylformamide (anhydrous, 100 mL) was added dropwise viaaddition funnel (keeping internal temp. below 5° C.) and the reactionmixture became a solution. Stirring @ 0° C. was continued for 45minutes, then the reaction was allowed to warm to RT; monitoring by TLC(silica gel, 1:3 ethyl acetate/hexane, UV, ninhydrin stain) of aquenched sample indicated that the reaction had progressed tocompletion. The mixture was poured onto ice (˜2 L) and stirred withaddition of EtOAc (2 L). The layers were separated and the organic layerwas dried over magnesium sulfate. The dried solution was filteredthrough a pad of 30/40 Magnesol and the filtrate was concentrated todryness in vacuo, then the residue was dissolved in a minimum volume ofdichloromethane and chromatographed on a plug of silica gel, elutingwith ethyl acetate/hexane, 0-50% ethyl acetate. The clean,product-containing fractions were combined and concentrated to drynessin vacuo, to afford the desired product as a white solid, 69.8 g (62%).A somewhat impure fraction provided additional material, 16.8 g (15%),bringing the total recovery to 86.6 g, (77%). ¹H-NMR (CD₃OD): δ 7.01(dd, 1H, J=3.0, 1.6 Hz), 6.82 (dd, 1H, J=4.4, 1.7 Hz), 6.19 (dd, 1H,J=4.2, 2.9 Hz), 4.88 (s, 1H, H₂O+NH—), 1.50 (br s, 9H, HN—BOC); MS:LC/MS (+esi), m/z=207.9 [M+H].

Step 3: Preparation of tert-Butyl(4-bromo-2-cyano-1H-pyrrol-1-yl)carbamate

A 1 L, 3-neck RB flask was fitted with a mechanical stirrer, nitrogeninlet, thermocouple/JKEM thermocontroller, and a dry-ice acetonitrilecooling. 2-Cyano-pyrrol-1-yl)-carbamic acid, tert-butyl ester (20 g,96.5 mmol) was added and dissolved in 350 mL acetonitrile. The resultingsolution and cooled to below −30° C. 1,3-Dibromo-5,5-dimethylhydantoin(13.79 g, 48.26 mmol) was added as a solid, and the reaction was allowedto warm to rt over 2 h. Analysis by RP-HPLC at 2 h indicated that about10% starting material remained. The reaction was cooled again to below−30° C. and treated with additional 1,3-dibromo-5,5-dimethylhydantoin(1.3 g, 4.8 mmol). The reaction was allowed to warm slowly to rt over 3h. Once RP-HPLC indicated that all starting material had been consumed,the reaction was diluted with 500 mL EtOAc and transferred to aseparatory funnel. The organic was washed with 1 N sodium carbonate,water and brine and then dried with sodium sulfate. Filtration of theorganic layer thru silica gel removed much of the colored impurities.Evaporation of the solvent under vacuum provided a reddish oil, whichprovided orange-brown crystals of the desired product upon seeding(27.16 g, 98% yield). This material proved to be only about 90% pure by¹H-NMR. ¹H-NMR (DMSO): δ 10.95 (bs, 1H), 7.61 (d, 1H, J=2.0 Hz), 7.16(d, 1H, J=2 Hz), 1.44 (s, 9H, J=4.4, 1.7 Hz).

Step 4: Preparation of 1-Amino-4-bromo-1H-pyrrole-2-carbonitrilehydrochloride

A 1 L, 3-neck RB flask was fitted with a mechanical stirrer, nitrogeninlet, thermocouple/JKEM thermocontroller, cooling bath and an additionfunnel. tert-Butyl (4-bromo-2-cyano-1H-pyrrol-1-yl)carbamate (19 g, 66mmol) was added and dissolved with 1,4-dioxane (50 mL), then the stirredorange solution was cooled to 0° C. and HCl/dioxane (4 N, 100 mL, 8 eq.)was slowly added from the addition funnel, maintaining an internaltemperature around 25° C. After 2 hours the solution became cloudy andstirring @ room temperature was continued for 7 hours; the reaction wasmonitored for completion by TLC (silica gel, GHLF, 1:3 EtOAc/hexane, UV;Note: the free base may be observed as a high-Rf spot and can bemisinterpreted as incomplete reaction). The reaction mixture was dilutedwith diethyl ether (150 mL) and the precipitated solids were collectedby suction filtration and washed with ether (200 mL). Drying (vacuumoven @ 50° C.) afforded the desired product as 10.9 g (93%) of a whitesolid. ¹H-NMR (DMSO): δ 7.24 (d, 1H, J=2 Hz), 6.93 (d, 1H, J=2 Hz), 6.2(bs, 3H, J=2.8, 4.4 Hz).

Step 5: Preparation of the Title Compound

To a stirred suspension of 1-Amino-4-bromo-1H-pyrrole-2-carbonitrilehydrochloride (17 g, 61.1 mmol) in absolute ethanol (350 mL) was addedformamidine acetate (31.8 g, 305 mmol) and potassium phosphate (64.9 g,305 mol). The suspension was heated for 18 hours @ 78° C. (under N2),then cooled, filtered and concentrated to dryness in vacuo. The residuewas mixed with ice water (2 L) and the dark grayish-brown solids werecollected by suction filtration. The solids were taken up in refluxingMeOH and treated with decolorizing carbon, then filtered thru Celite andconcentrated dryness in vacuo. The solids were taken up in THF:DCE (1:3)and filtered thru a pad of silica. Removal of the solvent in vacuoprovided a yellowish-brown solid. This material was recrystallized fromTHF:hexanes to provide the desired compound as a yellow solid (9.86 g,75% yield). (81%). ¹H-NMR (DMSO): δ 7.85 (bs, 2H), 7.81 (s, 1H), 7.80(d, 1H, J=2 Hz), 6.96 (d, 1H, J=2 Hz).

Intermediate AAF Preparation of1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[4-(trifluoromethyl)pyridin-2-yl]urea

To a solution of2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (8.00 g,33.7 mmol, 1 eq) (product of Step 1 Intermediate F (preparation 1)) in1,2-dichloroethane (80 ml) was added Intermediate V(phenyl[4-(trifluoromethyl)pyridin-2-yl]carbamate) (10.00 g, 35.4 mmol,1.05 eq). Triethylamine (4.70 ml, 33.7 mmol, 1 eq) was then added andreaction was allowed to stir at 60° C. for 4 hours. The reaction wascooled in an ice bath and the resulting white solids collected byfiltration. The solids were washed with 1,2-dichloroethane and hexanesthen dried under vacuum to obtain the desired product (10.86 g, 75.7%yield). ¹H-NMR (DMSO-δ6) δ 10.18 (s, 1H), 8.52 (d, J=5.2 Hz, 1H), 8.28(t, J=8.0 Hz, 1H), 7.97 (s, 1H), 7.46 (dd, =8.1, 1.0 Hz, 1H), 7.40-7.36(m, 2H), 1.27 (s, 12H); MS [M+H]⁺=426, LCMS RT=4.33 min.

The following boronates were prepared in the same manner as IntermediateF by substituting the appropriate bromide forN-(4-bromo-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]ureaand by substituting the appropriate isocyanate or carbamate for1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene.

LC-MS m/z [M + H], RT, Intermediate Structure IUPAC Name Method AAG

1-[4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl]-3-[4-(trifluoromethyl) pyridin-2-yl]urea 407.9, 3.93 min, A AAH

1-[2-fluoro-5- (trifluoromethyl) phenyl]-3-[2-methyl- 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl]urea 439.2, 3.81 min, A AAI

1-[2-methyl-4- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl]-3-[4- (trifluoromethyl) pyridin-2-yl]urea 422.2, 3.77 min,A AAJ

1-(2-fluoro-5- methylphenyl)-3-[2- fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan- 2-yl)phenyl]urea 389.3, 3.83 min, A AAK

1-[2-chloro-5- (trifluoromethyl) phenyl]-3-[2-fluoro- 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl]urea 459.1, 4.53 min, A AAL

1-[2-chloro-5- (trifluoromethyl) phenyl]-3-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan- 2-yl)phenyl]urea 441, 4.38 min, A AAM

2-methyl-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2- yl)aniline234.2, 3.06 min, A AAN

1-[2-fluoro-5- (trifluoromethyl) phenyl]-3-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan- 2-yl)phenyl]urea 425, 4.11 min, A AAO

1-[3-(trifluoro- methyl)phenyl]-3-[2- fluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl]urea 425, 4.24 min, A AAP

1-[3-(trifluoro- methyl)phenyl]-3-[2- chloro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl]urea 441, 4.48 min, A

Example 1 Preparation of Ethyl4-amino-7-(3-fluorophenyl)-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate

Palladium(II)acetate (0.002 g, 0.009 mmol) was dissolved in dioxane (0.5mL), and treated with triphenylphosphine (0.009 g, 0.035 mmol). Themixture was degassed twice before adding ethyl Intermediate AY(4-amino-7-bromo-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4-]triazine-6-carboxylate(0.05 g, 0.009 mmol)), 3-fluorophenylboronic acid (0.014 g, 0.097 mmol)and aq. Na₂CO₃ solution (0.11 mL, 0.22 mmol, 2M). The mixture was heatedto 80° C. overnight. The reaction was then cooled and filtered throughsilica. The filtrate was concentrated then triturated with EtOAc. Theproduct was collected by filtration to give 20 mg of a tan solid (39%).¹H-NMR (THF-d₈) δ 10.59 (bs, 1H) 9.08 (s, 1H), 8.47 (d, J=5.1, 1H), 7.79(s, 1H), 7.73-7.68 (m, 3H), 7.41-7.37 (m, 5H), 7.23 (d, J=5.2, 1H),7.13-7.08 (m, 1H), 3.94 (q, J=7.1, 2H), 0.90 (t, J=7.1, 3H); MS[M+H]⁺=580.0; LCMS RT=3.41.

Example 2 Preparation of Ethyl4-amino-7-(4-fluorophenyl)-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate

The procedure used for the preparation of Example 1 was used to preparethe title compound by substituting 4-fluorophenylboronic acid for-fluorophenylboronic acid. ¹H-NMR (THF-d₈) δ 9.08 (bs, 1H) 8.47 (d,J=5.5, 1H), 7.76 (s, 1H), 7.72-7.69 (m, 2H), 7.62 (d, J=8.5, J=5.6, 2H),7.39 (d, J=8.7, 2H), 7.23 (d, J=5.3, 1H), 7.14 (t, J=8.8, 3H) 3.92 (q,J=7.1, 2H), 0.89 (t, J=7.1, 3H); MS [M+H]⁺=579.9; LCMS RT=3.31.

Example 3 Preparation of ethyl4-amino-7-[3-(trifluoromethyl)phenyl]-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}-carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate

The procedure used for the preparation of Example 1 was used to preparethe title compound by substituting 3-fluorophenylboronic acid with(3-trifluoromethylphenyl)boronic acid. ¹H-NMR (THF-d₈) δ 9.08 (bs, 1H)8.47 (d, J=5.0, 1H), 7.94 (s, 1H), 7.86 (d, J=7.7, 2H), 7.79 (s, 1H),7.73-7.67 (m, 3H), 7.61 (d, J=7.7, 1H), 7.40 (d, J=8.5, 1H) 7.22 (d,J=5.0, 1H), 3.92 (q, J=7.1, 2H), 0.88 (t, J=7.1, 3H); MS [M+H]⁺=592.0;LCMS RT=3.26.

Example 4 Preparation of ethyl4-amino-7-(4-methoxyphenyl)-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]-phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate

The procedure used for the preparation of Example 1 was used to preparethe title compound by substituting 3-fluorophenylboronic acid with(4-methoxyphenyl)boronic acid. ¹H-NMR (THF-d₈) δ 9.07 (bs, 1H) 8.46 (d,J=5.2, 1H), 7.74 (s, 1H), 7.70 (d, J=8.7, 2H), 7.53 (d, J=8.9, 2H), 7.38(d, J=8.6, 2H), 7.22 (d, J=5.6, 1H), 6.94 (d, J=9.0, 2H) 3.92 (q, J=7.1,2H), 3.83 (s, 3H), 0.90 (t, J=7.1, 3H); MS [M+H]⁺=592.0; LCMS RT=3.20.

Example 5 Preparation of4-amino-7-cyano-5-4-[([2-fluoro-5-(trifluoromethyl)phenyl]aminocarbonyl)amino]phenyl-N-(2,2,2-trifluoroethyl)-pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide

To a solution of Intermediate AT(4-amino-7-bromo-5-{4-[({[2-fluoro-5-(trifluoromethyl)-phenyl]amino}carbonyl)amino]phenyl}-N-(2,2,2-trifluoroethyl)-pyrrolo-[2,1-f][1,2,4]triazine-6-carboxamide(46 mg, 0.07 mmol)) in 1-methyl-2-pyrrolidinone (3 ml) was added coppercyanide (I) (25 mg, 0.14 mmol). The reaction was heated at 170° C. in asealed tube for 2 h. After cooling to rt, ethyl acetate was added andthe mixture was washed with H₂O (3×). The combined organic layer wasdried (Na₂SO₄), concentrated and purified via column chromatography(95:5 v/v CH₂Cl₂-MeOH) to afford 13 mg of the above compound (yield30%). ¹H-NMR (DMSO-d₆) δ9.36 (s, 1H), 8.94 (d, J=3 Hz, 1H), 8.73 (m,1H), 8.61 to 8.58 (m, 1H), 8.20 (s, 1H), 7.57 (d, J=8 Hz, 2H), 7.31-50(m, 3H), 3.97 (m, 2H); MS [M+H]⁺=581.0; LCMS RT=3.37 min.

Example 6 Preparation of ethyl4-amino-7-cyano-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate

The procedure used for the preparation of Example 5 was used to preparethe title compound by substituting Intermediate AZ for Intermediate AT.¹H-NMR (DMSO-d₆) δ 9.98 (s, 1H), 9.79 (s, 1H), 8.58 (bs, 1H), 8.53 (d,J=5.4 Hz, 1H), 8.21 (S, 1H), 8.07 (s, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.36(m, 1H), 7.35 (d, J=8.4 Hz, 2H), 5.39 (bs, 1H), 4.11 (qt, J=6.9 Hz, 2H),1.07 (t, J=6.9 Hz, 3H); MS [M+H]⁺=511.1; LCMS RT=3.60.

Example 7 Preparation of4-amino-7-cyano-N-(2,2,2-trifluoroethyl)-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)-amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide

Step 1: Preparation of4-amino-7-bromo-N-(2,2,2-trifluoroethyl)-5-{-4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f]-[1,2,4]triazine-6-carboxamide

The procedure used for the preparation of Intermediate AT was used toprepare the title compound by substituting Intermediate AH forIntermediate T.

Step 2: Preparation of Title Compound

The procedure used for the preparation of Example 5 was used to preparethe title compound by substituting4-amino-7-bromo-N-(2,2,2-trifluoroethyl)-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f]-[1,2,4]-triazine-6-carboxamidefor Intermediate AT. ¹H-NMR (DMSO-d₆) δ 9.90 (s, 1H), 9.74 (s, 1H), 8.78(t, J=4.5 Hz, 1H), 8.20 (s, 1H), 8.05 (s, 1H), 7.60 (d, J=6.6 Hz, 2H),7.37 (m, 1H), 7.34 (d, J=7 Hz, 2H), 5.60 (bs, 1H), 4.04 to 3.95 (m, 2H);MS [M−H]⁺=564.0; LCMS RT=3.17.

Example 8 Preparation of4-amino-7-cyano-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylicacid

Step 1: Preparation of4-amino-7-bromo-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylicacid

The procedure used for the preparation of Intermediate AT was used toprepare the title compound by substituting Intermediate X forIntermediate T.

Step 2: Preparation of Title Compound

The procedure used for the preparation of Example 5 was used to preparethe title compound by substituting4-amino-7-bromo-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylicacid for Intermediate AT. ¹H-NMR (DMSO-d₆) δ 9.92 (s, 1H), 9.77 (s, 1H),8.53 (d, J=5.4 Hz, 1H), 8.19 (s, 1H), 8.06 (s, 1H), 7.60 (d, J=8.7 Hz,2H), 7.36 (d, J=8.7 Hz, 2H), 7.36 (m, 1H) 5.30 (bs, 1H); MS[M+H]⁺=483.0; LCMS RT=2.87.

Example 9 Preparation of4-amino-5-{4-[({[2-fluoro-5-(trifluoromethyl)-phenyl]amino}carbonyl)amino]phenyl}-7-(morpholin-4-ylmethyl)-N-(2,2,2-trifluoroethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide

To a suspension of Intermediate AU (4-amino-5-4-[([2-fluoro5(trifluoromethyl)phenyl]aminocarbonyl)amino]phenyl-7-formyl-N-(2,2,2-trifluoro-ethyl)pyrrolo[2,1-f]-[1,2,4]triazine-6-carboxamide(35 mg, 0.06 mmol)) and morpholine (0.013 ml, 0.015 mmol) indichloroethane (2 ml) was added sodium triacetoxyborohydride (50 mg,0.24 mmol). The reaction was stirred under N₂ at rt for 16 h. Thereaction mixture was diluted with CH₂Cl₂ and quenched with aq. saturatedNaHCO₃. The organic layer was collected, dried over (Na₂SO₄) andconcentrated by rotary evaporation. The crude was purified via columnchromatography (95:5 v/v CH₂Cl₂-MeOH) to afford 15.5 mg of the titlecompound (yield 39%). ¹H-NMR (DMSO-d₆) δ 9.98 (dd, J=6 Hz, 1H), 9.29 (s,1H), 8.95 (d, J=3 Hz, 1H), 8.64 to 8.61 (dd, J=3 Hz, 1H), 7.94 (s, 1H),7.53 to 7.46 (m, 2H), 7.36-7.46 (m, 1H), 7.28 (d, J=9 Hz, 2H), 4.06 to4.04 (m, 2H), 4.01 (s, 2H), 3.57 (d, J=7 Hz, 4H), 2.47 to 2.25 (m, 4H)ppm; MS [M+H]⁺=655.1; LCMS RT=2.64 min.

Example 10 Preparation of4-amino-5-{4-[({[2-fluoro-5-(trifluoromethyl)-phenyl]amino}carbonyl)amino]phenyl}-7-[(4-methylpiperazin-1-yl)methyl]-N-(2,2,2-trifluoroethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide

The procedure used for the preparation of Example 9 was used to preparethe title compound by substituting reagent N-methyl piperazine formorpholine. ¹H-NMR (MeOH-d₄) δ 8.61 (d, J=8 Hz, 1H), 7.88 (s, 1H), 7.58to 7.55 (m, 2H), 7.38 to 7.32 (m, 4H), 4.15 (s, 2H), 4.10 to 4.00 (m,2H), 2.63 to 2.46 (m, 8H), 2.30 (s, 3H); MS [M+H]⁺=668.0; LCMS RT=2.55min.

Example 11 Preparation ofN-4-[4-amino-7-cyano-6-(methoxy-methyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

To a solution of Intermediate AV(N-{4-[4-amino-7-bromo-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoro-methyl)phenyl]urea(500 mg, 0.90 mmol)) in 1-methyl-2-pyrrolidinone (3 ml) was added CuCN(321 mg, 1.80 mmol). The reaction was heated at 170° C. in a flask for 2h. After cooling to rt, EtOAc was added and the mixture was washed withH₂O (3×). The combined organic layer was dried (Na₂SO₄), concentratedand purified via column chromatography (95:5 v/v CH₂Cl₂-MeOH) to afford64 mg of the titled compound (yield 13%). ¹H-NMR (Acetone-d₆) δ38.85 (s,1H), 8.79 (d, J=8 Hz, 1H), 8.43 (s, 1H), 7.75 to 7.71 (m, 2H), 7.47 to7.38 (m, 4H), 4.39 (s, 2H), 3.31 (s, 3H); MS [M+H]⁺=500.1; LCMS RT=3.41min.

Example 12 Preparation ofN-{4-[4-amino-6-(methoxymethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a suspension of Intermediate AW(N-{4-[4-amino-7-formyl-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoro-methyl)phenyl]urea(50 mg, 0.1 mmol)) and morpholine (0.01 ml, 0.12 mmol) in dichloroethane(3 ml) was added sodium triacetoxyborohydride (67 mg, 0.31 mmol). Thereaction was stirred under N₂ at rt for 16 h. The reaction mixture wasdiluted with CH₂Cl₂ and subsequently quenched with aqueous saturatedNaHCO₃. The organic phase was collected, dried (Na₂SO₄), concentratedand purified via column chromatography (95:5 v/v CH₂Cl₂-MeOH) to afford26 mg of the title compound (yield 46%). ¹H-NMR (DMSO-d₆) δ9.32 (s, 1H),8.96 (d, J=2 Hz, 1H), 8.64 to 8.61 (dd, J=8, 2 Hz, 1H), 7.90 (s, 1H),7.59 to 7.34 (m, 6H), 4.29 (s, 2H), 3.86 (s, 2H), 3.55 to 3.50 (m, 4H),3.14 (s, 3H), 2.47-2.41 (m, 4H); MS [M+H]⁺=573.9; LCMS RT=2.53 min.

Example 13 Preparation ofN-(4-{4-amino-6-(methoxymethyl)-7-[(4-methylpiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[2-fluoro-5-(trifluoro-methyl)phenyl]urea

The procedure used for the preparation of Example 12 was used to preparethe title compound by substituting N-methyl piperazine for morpholine.¹H-NMR (MeOH-d₄) δ 8.62 (d, J=8 Hz, 1H), 7.83 (s, 1H), 7.63 to 7.59 (m,2H), 7.42 to 7.32 (m, 4H), 4.39 (s, 2H), 4.01 (s, 2H), 3.27 (s, 3H),2.64 to 2.43 (br, 8H), 2.25 (s, 3H); MS [M+H]⁺=587.0; LCMS RT=2.37 min.

Example 14 Preparation ofN-{4-[4-amino-6-(methoxymethyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 12 was used to preparethe title compound by substituting pyrrolidine for morpholine. ¹H-NMR(MeOH-d₄) δ58.62 (d, J=8 Hz, 1H), 7.90 (s, 1H), 7.65 to 7.62 (m, 2H),7.42 to 7.33 (m, 4H), 4.42 (s, 4H), 3.29 (s, 3H), 3.00 (s, 4H), 1.96 to1.90 (m, 4H); MS [M+H]⁺=558.0; LCMS RT=2.49 min.

Example 15 Preparation ofN-{4-[4-amino-7-{[(2-methoxyethyl)amino]methyl}-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 12 was used to preparethe title compound by substituting reagent methoxyethylamine formorpholine. ¹H-NMR (DMSO-d₆) δ9.34 (s, 1H), 8.96 (d, J=3 Hz, 1H), 8.64to 8.61 (m, 1H), 7.90 (s, 1H), 7.60 to 7.31 (m, 6H), 4.27 (s, 2H), 4.05(s, 2H), 3.40-3.34 (m, 2H), 3.18 (s, 3H), 3.16 (s, 3H); MS [M+H]⁺=561.9;LCMS RT=2.51 min.

Example 16 Preparation ofN-{4-[4-amino-7-[(cyclopropylamino)methyl]-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 12 was used to preparethe title compound by substituting reagent cyclopropylamine formorpholine. ¹H-NMR (CH₃OH-d₄) δ8.62 (d, J=6 Hz, 1H), 7.86 (s, 1H), 7.64to 7.60 (m, 2H), 7.42 to 7.32 (m, 4H), 4.40 (s, 2H), 4.22 (s, 2H), 3.36(s, 3H), 2.14 to 2.09 (m, 1H), 0.52 to 0.40 (m, 4H) ppm; MS[M+H]⁺=543.9; LCMS RT=2.45 min

Example 17 Preparation ofN-{4-[4-amino-7-{[bis(2-methoxyethyl)-amino]methyl}-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 12 was used to preparethe title compound by substituting N-(2-methoxyethyl)methylamine formorpholine. ¹H-NMR (DMSO-d₆) δ 9.32 (s, 1H), 8.96 (d, J=3 Hz, 1H), 8.63(dd, J=8, 3 Hz, 2H), 7.89 (s, 1H), 7.58 (d, J=8 Hz, 2H), 7.50 to 7.33(m, 3H), 4.31 (s, 2H), 4.03 (s, 2H), 3.20 to 3.40 (m, 13H), 2.6 (t, J=5Hz, 4H) ppm; MS [M+H]⁺=619.9; LCMS RT=2.69 min.

Example 18 Preparation ofN-{4-[4-amino-7-[(2,6-dimethylmorpholin-4-yl)methyl]-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 12 was used to preparethe title compound by substituting 2,4-dimethylmorpholine formorpholine. ¹H-NMR (CH₃OH-d₄) δ8.63 (dd, J=6, 1 Hz, 1H), 7.84 (s, 1H),7.62 (dd, J=6, 2 Hz, 2H), 7.42 (dd, J=6, 2 Hz, 2H), 7.34 (dd, J=7, 2 Hz,2H), 4.39 (s, 2H), 3.99 (s, 2H), 3.68 to 3.63 (m, 2H), 3.28 (s, 3H),2.86 (d, J=11 Hz, 2H), 1.91 (t, J=11 Hz, 2H), 1.1 (d, J=6 Hz, 6H) ppm;MS [M+H]⁺=602.0; LCMS RT=2.73 min.

Example 19 Preparation ofN-(4-{4-amino-6-(methoxymethyl)-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 12 was used to preparethe title compound by substituting 2-oxopiperizine for morpholine.¹H-NMR (DMSO-d₆) δ9.32 (s, 1H), 8.96 (d, J=3 Hz, 1H), 8.62 (dd, J=7, 2Hz, 1H), 7.91 (s, 1H), 7.70 (s, 1H), 7.60 (d, J=3 Hz, 2H), 7.57 to 7.35(m, 3H), 4.29 (s, 2H), 3.93 (s, 2H), 3.19 (s, 3H), 3.09 (m, 2H), 2.98(m, 2H), 2.62 (m, 2H) ppm; MS [M+H]⁺=587; LCMS RT=2.59 min.

Example 20 Preparation ofN-[4-(4-amino-6-(methoxymethyl)-7-{[4-(methylsulfonyl)piperazin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 12 was used to preparethe title compound by substituting 1-(methylsulfonyl)piperazine formorpholine. ¹H-NMR (CH₃OH-d₄) δ8.62 (dd, J=7, 1 Hz, 1H), 7.84 (s, 1H),7.64 to 7.61 (m, 2H), 7.43 to 7.41 (m, 4H), 4.39 (s, 2H), 4.03 (s, 3H),3.21 (t, J=5 Hz, 4H), 2.81 (s, 3H), 2.66 (t, J=5 Hz, 4H) ppm; MS[M+H]⁺=651; LCMS RT=2.61 min.

Example 21 Preparation ofN-{4-[7-[(4-acetylpiperazin-1-yl)methyl]-4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 12 was used to preparethe title compound by substituting 1-acetylpiperazine for morpholine.¹H-NMR (CH₃OH-d₄) δ 8.62 (d, J=3 Hz, 1H), 7.82 (s, 1H), 7.62 (d, J=5 Hz,2H), 7.42 (d, J=5 Hz, 2H), 7.38 (d, J=5 Hz, 2H), 4.42 (s, 2H), 4.02 (s,2H), 3.58 to 3.44 (m, 4H), 2.62 to 2.58 (m, 4H), 2.08 (s, 3H) ppm; MS[M+H]⁺=614.9; LCMS RT=2.58 min.

Example 22 Preparation ofN-{4-[4-amino-7-{[(2-methoxyethyl)-(methyl)amino]methyl}-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 12 was used to preparethe title compound by substituting 2-methoxy-N-methylethanamine formorpholine. ¹H-NMR (DMSO-d₆) δ9.32 (d, 1H), 8.96 (d, J=2 Hz, 1H), 8.63(dd, J=7 Hz, 1H), 7.89 (s, 1H), 7.58 (d, J=8 Hz, 2H), 7.50 to 7.34 (m,4H), 4.30 (s, 2H), 3.89 (br, 2H), 3.46 to 3.48 (m, 2H), 3.20 (s, 3H),3.16 (s, 3H), 2.58 to 2.55 (m, 2H), 2.17 (s, 3H) ppm; MS [M+H]⁺=575.9;LCMS RT=2.57 min.

Example 23 Preparation ofN-{4-[4-amino-7-(hydroxymethyl)-6-(methoxymethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

To a solution of Intermediate AW(N-{4-[4-amino-7-formyl-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoro-methyl)phenyl]urea(50 mg, 0.1 mmol)) in THF at −78° C. under N₂ was added DIBAL-H (0.5 ml,0.5 mmol). The reaction mixture was stirred for 30 min. and was allowedto warm up to 0° C. The reaction was diluted with ethyl acetate (5 mL)and quenched with aqueous saturated Rochelle's salt (5 ml). The reactionmixture was stirred for 10 min at 0° C. and then warmed to rt. Theorganic layer was collected and washed with aqueous Rochelle's salt(2×), dried (Na₂SO₄) and concentrated. The crude concentrate waspurified via column chromatography (5:95, v/v MeOH—CH₂Cl₂) to afford 25mg of the title compound (yield 49%). ¹H-NMR (DMSO-d₆) δ9.32 (s, 1H),8.96 (d, J=3 Hz, 1H), 8.63 (d, J=5 Hz, 1H), 7.90 (s, 1H), 7.58 (d, J=7Hz, 2H), 7.50 to 7.32 (m, 3H), 5.0 (t, J=5 Hz, 1H), 4.79 (d, J=5 Hz,2H), 4.30 (s, 3H), 3.16 (s, 2H) ppm; MS [M+H]⁺=505.1; LCMS RT=2.66 min.

Example 24 Preparation ofN-{4-[4-amino-6,7-bis(methoxymethyl)pyrrolo[2,1-f]-[1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a solution of Example 23(N-{4-[4-amino-7-(hydroxymethyl)-6-(methoxy-methyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoro-methyl)-phenyl]urea(22 mg, 0.04 mmol)) in anhydrous THF (1 mL) and CH₂Cl₂ (1 mL) was addedSOCl₂ (0.006 ml, 0.08 mmol). After 20 min, analytical HPLC shoved halfof the starting material remained. Additional SOCl₂ (0.01 ml) was addedand the reaction was stirred at rt for 2.5 h until completion. Themixture was evaporated to dryness and CH₂Cl₂ (3 ml) was added. Thesolvent was evaporated to dryness and the crude concentrate wasre-suspended in CH₂Cl₂ and evaporated to remove the excess SOCl₂completely. To the resulting solid was added anhydrous MeOH (1 ml) andHunig's base (0.008 ml), the reaction was stirred at 70° C. overnight.After 16 h, the reaction was cooled to rt and solvent was evaporated.The crude material was taken up in ethyl acetate, washed with aq.saturated sodium bicarbonate three times and dried over Na₂SO₄. Afterconcentration, the resulting crude was purified via columnchromatography (5:95 v/v MeOH—CH₂Cl₂) to afford 12 mg of the titlecompound (yield 53%). ¹H-NMR (DMSO-d₆) δ 9.32 (s, 1H), 8.96 (d, J=3 Hz,1H), 8.63 (dd, J=7, 3 Hz, 1H), 7.92 (s, 1H), 7.59 (t, J=3 Hz, 2H), 7.57to 7.32 (m, 4H), 4.73 (s, 2H), 4.28 (s, 2H), 3.26 (s, 3H), 3.24 (s, 3H)ppm; MS [M+H]⁺=519.1; LCMS RT=2.84 min

Example 25 Preparation ofN-{4-[4-amino-7-(1-hydroxyethyl)-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a solution of Intermediate AW(N-{4-[4-amino-7-formyl-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoro-methyl)phenyl]urea(25 mg, 0.05 mmol)) in THF (1 ml) at −78 C under N₂ was addedmethyllithium (0.18 ml, 0.25 mmol) and stirred for 10 min. The reactionwas quenched by the addition of H₂O and after warming to rt, thereaction mixture was extracted with ethyl acetate. The organic layer wasdried (Na₂SO₄), concentrated and purified via column chromatography(5:95 v/v MeOH—CH₂Cl₂) to afford 13 mg of the title compound (yield50%). ¹H-NMR (DMSO-d₆) δ9.32 (s, 1H), 8.97 (d, J=2 Hz, 1H), 8.63 (dd,J=8, 2 Hz, 1H), 7.87 (s, 1H), 7.55 (d, J=8 Hz, 2H), 7.53 to 7.31 (m,4H), 5.49 to 5.45 (m, 1H), 5.19 (d, J=6 Hz, 1H), 4.52 (d, J=10 Hz, 1H),4.19 (d, J=10 Hz, 1H), 3.16 (s, 3H), 1.50 (d, J=6 Hz, 3H) ppm; MS[M+H]⁺=519.1; LCMS RT=2.74 min.

Example 26 Preparation ofN-4-[4-amino-7-(morpholin-4-ylmethyl)-6-(1,3-oxazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a solution of formaldehyde (37% solution in water, (14 uL, 0.19 mmol)and morpholine (12 ul, 0.19 mmol) in AcOH (0.5 mL) was added to astirring solution of Intermediate Q in AcOH (1 mL). The reaction washeated to 60° C. overnight. The solvent was removed under vacuum and theresidue was dissolved in DCM and washed with sat. NaHCO₃ and brine. Theorganic layer was collected, dried, and concentrated under vacuum. Thecrude material was purified by silica gel chromatography using 100%EtOAc. The product fractions were collected and the solvent removedunder vacuum to give Example 60 (46% yield). ¹H-NMR (DMSO-d₆) δ 9.35 (s,1H), 9.00 to 8.95 (m, 1H), 8.363 to 8.59 (m, 1H), 8.28 (s, 1H), 7.96 (s,1H), 7.93 (br s, 1H), 7.59 to 7.54 (m, 2H), 7.52-7.46 (m, 1H), 7.41 to7.36 (m, 1H), 7.34 to 7.29 (m, 2H), 6.93 (s, 1H), 5.07 (br s, 1H), 3.94(s, 2H), 3.54 to 3.47 (m, 4H), 2.44 to 2.36 (m, 4H); MS [M+H]⁺=597.0;LCMS RT=2.45.

Example 27 Preparation ofN-4-[4-amino-7-(morpholin-4-ylmethyl)-6-(1,3-oxazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Example 26 was used to preparethe title compound by substituting Intermediate AG for Intermediate Q.¹H-NMR (DMSO-d₆) δ 9.94 (s, 1H), 9.79 (s, 1H), 8.53 (d, J=5.3, 1H), 8.27(s, 1H), 8.04 (s, 1H), 7.96 (s, 1H), 7.93 (br s, 1H), 7.63 to 7.58 (m,2H), 7.36 (d, J=5.3 (1H), 7.34 to 7.31 (m, 2H), 6.93 (s, 1H), 5.09 (brs, 1H), 3.93 (s, 2H), 3.52 to 3.47 (m, 4H), 2.43 to 2.37 (m, 4H); MS[M+H]⁺=579.9; LCMS RT=2.42.

Example 28 Preparation ofN-4-[4-amino-7-(morpholin-4-ylmethyl)-6-(1,3-oxazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[3-(trifluoromethoxy)-phenyl]urea

Step 1: Preparation ofN-{4-[4-amino-6-(1,3-oxazol-5-yl)pyrrolo[2,1-f][1,2,4]-triazin-5-yl]phenyl}-N′-[3-(trifluoromethoxy)phenyl]urea

The sequence of procedures used for the preparation of Intermediate Owas used to prepareN-{4-[4-amino-6-(1,3-oxazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[3-(trifluoromethoxy)phenyl]ureaby substituting the initial core Intermediate H for initial coreintermediate I. ¹H-NMR (DMSO-d₆) δ 9.11 (s, 1H), 9.02 (s, 1H), 8.30 (s,1H), 8.08 (s, 1H), 7.90 (s, 1H), 7.71 (s, 1H), 7.62 to 7.60 (d, J=8.4Hz, 2H), 7.42 to 7.38 (t, J=8.1 Hz, 1H), 7.36 to 7.34 (d, J=8.7 Hz, 2H),7.32 to 7.29 (d, J=9.1 Hz, 1H), 6.96 to 6.93 (d, J=10.6, 1H), 6.55 (s,1H); MS [M+H]⁺=496.1; LCMS RT=2.89 min.

Step 2: Preparation of Title Compound

The procedure used for the preparation of Example 26 was used to preparethe title compound by substitutingN-{4-[4-amino-6-(1,3-oxazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[3-(trifluoromethoxy)phenyl]ureafor Intermediate Q. ¹H-NMR (DMSO-d₆) δ 9.13 (s, 1H), 8.99 (s, 1H), 8.28(s, 1H), 7.96 (s, 1H), 7.91 (br s, 1H), 7.71 to 7.69 (m, 1H), 7.57 to7.53 (m, 2H), 7.38 (t, J=8.4, 1H), 7.32 to 7.37 (m, 3H), 6.95 to 6.91(m, 2H). 5.07 (br s, 1H), 3.93 (s, 2H), 3.53 to 3.47 (m, 4H), 2.43 to2.37 (m, 4H); MS [M+H]⁺=594.9; LCMS RT=2.57.

Example 29 Preparation ofN-4-[4-amino-7-(morpholin-4-ylmethyl)-6-(1,3-oxazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[3-fluoro-5-(trifluoromethyl)phenyl]urea

Step 1: Preparation ofN-{4-[4-amino-6-(1,3-oxazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[3-fluoro-5-(trifluoromethyl)phenyl]urea

The sequence of procedures used for the preparation of Intermediate Owas used to prepareN-{4-[4-amino-6-(1,3-oxazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[3-fluoro-5-(trifluoromethyl)phenyl]ureaby substituting the initial core Intermediate H for initial coreintermediate I. ¹H-NMR (CD₃OD) δ 8.12 (s, 1H), 7.97 (s, 1H), 7.83 (s,1H), 7.71 to 7.60 (m, 4H), 7.42 (d, J=8.2 Hz, 2H), 7.05 (d, J=8.1 Hz,1H), 6.49 (s, 1H); MS [M+H]⁺=498.2; LCMS RT=2.90.

Step 2: Preparation of Title Compound

The procedure used for the preparation of Example 26 was used to preparethe title compound by substitutingN-{4-[4-amino-6-(1,3-oxazol-5-yl)pyrrolo[2,1-f]-[1,2,4]triazin-5-yl]phenyl}-N′-[3-fluoro-5-(trifluoromethyl)phenyl]ureafor Intermediate Q. ¹H-NMR (DMSO-d₆) δ 9.36 (s, 1H), 9.14 (s, 1H), 8.28(s, 1H), 7.96 (s, 1H), 7.94 (br s, 1H), 7.71 (s, 1H), 7.64 to 7.59 (m,1H), 7.58 to 7.54 (m, 2H), 7.33 to 7.28 (m, 2H), 7.25 to 7.20 (m, 1H),6.92 (s, 1H), 5.07 (br s, 1H), 3.93 (s, 2H), 3.54 to 3.46 (m, 4H), 2.44to 2.36 (m, 4H); MS [M+H]⁺=569.9; LCMS RT=2.63.

Example 30 Preparation ofN-4-[4-amino-7-[(2,6-dimethylmorpholin-4-yl)methyl]-6-(1,3-oxazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 26 was used to preparethe title compound by substituting 2,4-dimethylmorpholine formorpholine. ¹H-NMR (DMSO-d₆) δ 9.35 (s, 1H), 8.97 (d, J=2.4, 1H), 8.62to 8.59 (m, 1H), 8.27 (s, 1H), 7.97 (s, 1H), 7.91 (br s, 1H), 7.58 to7.53 (m, 2H), 7.52 to 7.46 (m, 1H), 7.41 to 7.36 (m, 1H), 7.33 to 7.29(m, 2H), 6.94 (s, 1H), 5.05 (br s, 1H), 3.90 (s, 2H), 3.50 to 3.42 (m,2H), 2.65 (d, J=10.9, 2H), 1.76 (t, J=10.9, 2H), 1.01 (s, 3H), 0.99 (s,3H); MS [M+H]⁺=625.0; LCMS RT=2.69.

Example 31 Preparation ofN-4-[4-amino-7-[(4-methylpiperazin-1-yl)methyl]-6-(1,3-oxazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 26 was used to preparethe title compound by substituting N-methyl piperazine for morpholine.¹H-NMR (DMSO-d₆) δ 9.34 (s, 1H), 8.97 (d, J=2.4, 1H), 8.63 to 8.59 (m,1H), 8.27 (s, 1H), 7.45 (s, 1H), 7.58 to 7.54 (m, 2H), 7.52 to 7.46 (m,1H), 7.41 to 7.36 (m, 1H), 7.33 to 7.29 (m, 2H), 6.94 (s, 1H)., 3.92 (s,2H), 2.46 to 2.16 (m, 8H), 2.10 (s, 3H); MS [M+H]⁺=610.0; LCMS RT=2.49.

Example 32 Preparation ofN-4-[7-[(4-acetylpiperazin-1-yl)methyl]-4-amino-6-(1,3-oxazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 26 was used to preparethe title compound by substituting 1-acetylpiperazine for morpholine.¹H-NMR (DMSO-d₆) δ 9.34 (s, 1H), 8.97 (d, J=2.4, 1H), 8.63 to 8.59 (m,1H), 8.28 (s, 1H), 7.96 (s, 1H), 7.92 (br s, 1H), 7.58 to 7.54 (m, 2H),7.53 to 7.47 (m, 1H), 7.41 to 7.36 (m, 1H), 7.34 to 7.30 (m, 2H), 6.91(s, 1H), 5.09 (br s, 1H), 3.97 (s, 2H), 3.39 to 3.32 (m, 4H), 2.44 to2.39 (m, 2H), 2.38 to 2.33 (m, 2H); MS [M+H]⁺=637.9; LCMS RT=2.57.

Example 33N-4-[4-amino-7-(morpholin-4-ylmethyl)-6-(1,3-oxazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Example 26 was used to preparethe title compound by substituting Intermediate AK(N-{4-[4-amino-6-(1,3-oxazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea)for Intermediate Q. ¹H-NMR (DMSO-d₆) δ 10.16 (s, 1H), 10.12 (br s, 1H),8.53 (d, J=4.4 Hz, 1H), 8.29 (m, 1H), 8.28 (m, 1H), 7.99 (br s, 1H),7.97 (m, 1H), 7.38 (d, J=2.2 Hz, 1H), 7.31 (d, J=12.4 Hz, 1H), 7.16 (d,J=8.2 Hz, 1H), 7.00 (m, 1H), 3.92 (s, 2H), 3.51 (m, 4H), 2.41 (m, 4H);MS [M+H]⁺=598.0; LCMS RT=2.89.

Example 34N-4-[4-amino-6-(hydroxymethyl)-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

The procedure used for the preparation of Example 26 was used to preparethe title compound by substituting Intermediate K(N-{4-[4-amino-6-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]-triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoro-methyl)phenyl]-urea)for Intermediate Q. ¹H-NMR (DMSO-d₆) δ 9.35 (s, 1H), 8.98 (d, J=2.7 Hz,1H), 8.64 (dd, J=7.3, 2.5 Hz, 1H), 7.91 (s, 1H), 7.60 (m, 2H), 7.52 (m,1H), 7.41 (m, 1H), 7.39 (m, 2H), 5.08 (br s, 1H), 4.40 (s, 2H), 3.95 (s,2H), 3.53 (m, 4H), 2.45 (m, 4H); MS [M+H]⁺=560.0; LCMS RT=2.43.

Example 35 Preparation ofN-4-[4-amino-6-(methoxymethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Example 26 was used to preparethe title compound by substituting Intermediate Z for Intermediate Q.¹H-NMR (DMSO-d₆) δ 9.91 (s, 1H), 9.76 (s, 1H), 8.46 to 8.58 (m, 1H),8.03 (s, 1H), 7.88 (s, 1H), 7.54 to 7.71 (m, 2H), 7.28 to 7.45 (m, 3H),4.29 (s, 2H), 3.85 (s, 2H), 3.44 to 3.63 (m, 4H), 3.17 (s, 3H), 2.35 to2.50 (m, 4H). MS [M+H]⁺=556.91; LCMS RT=2.35.

Example 36N-4-[4-amino-7-[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Example 26 was used to preparethe title compound by substituting Intermediate Z for Intermediate Q andby substituting 2,4-dimethylmorpholine for morpholine. ¹H-NMR (DMSO-d₆)δ 9.89 (s, 1H), 9.75 (s, 1H), 8.48 to 8.59 (m, 1H), 8.04 (s, 1H), 7.89(s, 1H), 7.53 to 7.70 (m, 2H), 7.25 to 7.47 (m, 3H), 4.29 (s, 2H), 3.84(s, 2H), 3.41 to 3.59 (m, 2H), 3.18 (s, 3H), 2.68 to 2.85 (d, J=9.6 Hz,2H), 1.67 to 1.87 (m, 2H), 0.99-1.07 (d, J=6.8 Hz, 6H). MS[M+H]⁺=584.90; LCMS RT=2.58.

Example 37N-4-[7-[(4-acetylpiperazin-1-yl)methyl]-4-amino-6-(methoxy-methyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Example 26 was used to preparethe title compound by substituting Intermediate Z for Intermediate Q andby substituting N-methyl piperazine for morpholine. ¹H-NMR (CD3OD-d₆) δ8.49 to 8.55 (d, J=5 Hz, 1H), 7.84 (s, 1H), 7.75 (s, 1H), 7.66 to 7.72(m, 2H), 7.40 to 7.48 (m, 2H), 7.26 to 7.30 (d, J=5 Hz, 1H), 4.42 (s,2H), 4.04 (s, 2H), 3.50 to 3.64 (m, 4H), 3.27 (s, 3H), 2.54 to 2.67 (m,4H), 2.09 (s, 3H). MS [M+H]⁺=597.98; LCMS RT=2.43.

Example 38N-[4-(4-amino-6-(methoxymethyl)-7-[(2R)-2-(methoxy-methyl)pyrrolidin-1-yl]methylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Example 26 was used to preparethe title compound by substituting Intermediate Z for Intermediate Q andby substituting (2R)-2-(methoxymethyl)pyrrolidine for morpholine. ¹H-NMR(DMSO-d₆) δ 9.89 (s, 1H), 9.77 (s, 1H), 8.49 to 8.57 (d, J=5 Hz, 1H),8.05 (s, 1H), 7.87 (s, 1H), 7.58 to 7.66 (m, 2H), 7.31 to 7.42 (m, 3H),4.18 (m, 2H), 3.86 to 3.96 (d, J=12.8 Hz, 1H), 3.37 to 3.45 (m, 1H),3.25 (s, 3H), 3.18 (s, 3H), 2.69 to 2.83 (m, 2H), 2.28 to 2.41 (m, 2H),1.77 to 1.91 (m, 1H), 1.42 to 1.69 (m, 3H). MS [M+H]⁺=584.95; LCMSRT=2.54.

Example 39 Preparation ofN-[4-(4-amino-6-(methoxymethyl)-7-{[4-(trifluoro-methyl)piperidin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Example 26 was used to preparethe title compound by substituting Intermediate Z for Intermediate Q andby substituting 4-(trifluoromethyl)piperidine for morpholine. ¹H-NMR(DMSO-d₆) δ 9.99 (s, 1H), 9.85 (s, 1H), 8.54 (d, J=5.2, 1H), 8.07 (s,1H), 7.91 (s, 1H), 7.64 (d, J=8.8, 2H); 7.39 to 7.36 (m, 3H), 4.29 (s,2H), 3.89 (s, 2H), 3.17 (s, 3H), 2.94 (d, J=11.2, 2H), 2.26 to 2.22 (m,1H), 2.08 (t, J=10.8, 2H), 1.75 (d, J=12.8, 2H), 1.39 (dq, J=8.4, 3.6,2H); MS [M+H]⁺=623.2; LCMS RT=3.01.

Example 40 Preparation ofN-{4-[4-amino-7-[(4,4-difluoropiperidin-1-yl)methyl]-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Example 26 was used to preparethe title compound by substituting Intermediate Z for Intermediate Q andby substituting 4,4-difluoropiperidine for morpholine. ¹H-NMR (DMSO-d₆)δ 10.06 (s, 1H), 9.93 (s, 1H), 8.54 (d, J=5.2, 1H), 8.08 (s, 1H), 7.91(s, 1H), 7.64 (d, J=8.8, 2H); 7.39 to 7.36 (m, 3H), 4.30 (s, 2H), 3.95(s, 2H), 3.18 (s, 3H), 2.58 to 2.57 (m, 4H), 2.01 to 1.82 (m, 4H); MS[M+H]⁺=591.1; LCMS RT=2.98.

Example 41 Preparation ofN-(4-{4-amino-6-(methoxymethyl)-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Example 26 was used to preparethe title compound by substituting Intermediate Z for Intermediate Q andby substituting 2-oxopiperizine for morpholine. (DMSO-d₆) δ 8.52 (d,J=5.6, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.66 (d, J=8.4, 2H); 7.38 to7.31 (m, 3H), 4.30 (s, 2H), 3.95 (s, 2H), 3.18 (s, 3H), 3.10 (t, J=5.2,2H), 3.00 (s, 2H), 2.63 (t, J=5.2, 2H); MS [M+H]⁺=570.1; LCMS RT=2.86.

Example 42 Preparation ofN-{4-[4-amino-7-{[4-(methoxyacetyl)piperazin-1-yl]methyl}-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Example 26 was used to preparethe title compound by substituting Intermediate Z for Intermediate Q andby substituting 1-(methoxyacetyl)piperazine for morpholine. ¹H-NMR(DMSO-d₆) δ 9.92 (s, 1H), 9.78 (s, 1H), 8.55 (d, J=4.8, 1H), 8.07 (s,1H), 7.92 (s, 1H), 7.64 (d, J=8.4, 2H); 7.40 to 7.37 (m, 3H), 4.30 (s,2H), 4.05 (s, 2H), 3.90 (s, 2H), 3.40 to 3.36 (m, 4H), 3.25 (s, 3H),3.18 (s, 3H), 2.46 to 2.41 (m, 4H); MS [M+H]⁺=628.1; LCMS RT=2.48.

Example 43 Preparation ofN-{4-[4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 26 was used to preparethe title compound by substituting Intermediate AB for Intermediate Qand by substituting thiomorpholine 1,1-dioxide for morpholine. ¹H-NMR(DMSO-d₆) δ 9.48 (s, 1H), 9.33 (s, 1H), 8.66 (dd, J=7.2, 2.0, 1H), 8.30(t, J=8.4, 1H), 7.94 (s, 1H), 7.52 (t, J=9.2, 1H); 7.43 to 7.40 (m, 1H),7.34 (dd, J=12.0, 2.0, 1H), 7.20 (dd, J=8.4, 1.2, 1H), 4.31 (s, 2H),4.08 (s, 2H), 3.21 (s, 3H), 3.09 (d, J=5.6, 4H), 2.98 (d, J=5.6, 4H); MS[M+H]⁺=640.1; LCMS RT=2.87.

Example 44 Preparation ofN-(4-{4-amino-6-(methoxymethyl)-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 26 was used to preparethe title compound by substituting Intermediate AB for Intermediate Qand by substituting 2-oxopiperizine for morpholine. ¹H-NMR (DMSO-d₆) δ9.45 (s, 1H), 9.30 (s, 1H), 8.67 (dd, J=7.2, 2.4, 1H), 8.30 (t, J=8.8,1H), 7.94 (s, 1H), 7.52 (t, J=9.2, 1H); 7.43 to 7.40 (m, 1H), 7.35 (dd,J=12.8, 2.0, 1H), 7.21 (dd, J=7.6, 1.6, 1H), 4.31 (s, 2H), 3.95 (s, 2H),3.20 (s, 3H), 3.10 (t, J=6.0, 2H), 2.99 (s, 2H), 2.63 (t, J=5.2, 2H); MS[M+H]⁺=605.0; LCMS RT=2.59.

Example 45 Preparation ofN-{4-[4-amino-6-(methoxymethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 26 was used to preparethe title compound by substituting Intermediate AB for Intermediate Q.¹H-NMR (DMSO-d₆) δ 8.64 (dd, J=7.2, 2.0, 1H), 8.26 (t, J=8.8, 1H), 7.92(s, 1H), 7.51 (t, J=8.8, 1H); 7.42 to 7.38 (m, 1H), 7.33 (dd, J=12.0,1.6, 1H), 7.19 (dd, J=8.4, 1.6, 1H), 4.31 (s, 2H), 3.87 (s, 2H), 3.52(t, J=4.0, 4H), 3.20 (s, 3H), 2.43 (t, J=4.0, 4H); MS [M+H]⁺=591.9; LCMSRT=2.74.

Example 46 Preparation ofN-{4-[4-amino-7-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluoro-phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 26 was used to preparethe title compound by substituting Intermediate AB for Intermediate Qand by substituting 2,4-dimethylmorpholine for morpholine. ¹H-NMR(CD3OD-d₄) δ 9.16 to 9.15 (m, 1H), 9.09 to 9.08 (m, 1H), 8.65 (d, J=8.0,1H), 8.36 (t, J=8.4, 1H), 8.11 (s, 1H), 7.37 to 7.33 (m, 3H), 7.27 (d,J=8.0, 1H); 4.86 (s, 2H), 4.46 (s, 2H), 9.93 to 9.79 (m, 2H), 3.56 (d,J=12.4, 2H), 3.40 (s, 3H), 3.24 (d, J=12.0, 2H), 1.24 (d, J=6.4, 6H); MS[M+H]⁺=619.8; LCMS RT=2.73.

Example 47 Preparation ofN-{4-[4-amino-7-{[2-(hydroxymethyl)morpholin-4-yl]methyl}-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

The procedure used for the preparation of Example 26 was used to preparethe title compound by substituting Intermediate AB for Intermediate Qand by substituting morpholin-2-ylmethanol for morpholine. ¹H-NMR(DMSO-d₆) δ 9.57 to 9.52 (m, 1H), 9.41 to 9.37 (m, 1H), 8.67 (dd, J=6.8,1.6, 1H); 8.31 (t, J=8.8, 1H), 7.99 (s, 1H), 7.52 (t, J=8.8, 1H), 7.44to 7.41 (m, 1H), 7.33 (d, J=12.4, 1H), 7.21 (d, J=8.8, 1H), 4.82 (s,2H), 4.79 to 4.74 (m, 1H), 4.55 (s, 2H), 4.19 to 4.10 (m, 4H), 3.69 (d,J=10.8, 2H), 3.18 (s, 3H), 2.90 (d, J=10.4, 1H), 2.77 (d, J=10.4, 1H);MS [H+H]⁺=622.1; LCMS RT=2.70.

Example 48 Preparation ofN-(4-{4-amino-6-(methoxymethyl)-7-[(4-methylpiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 26 was used to preparethe title compound by substituting Intermediate AB for Intermediate Qand by substituting N-methyl piperazine for morpholine. ¹H-NMR(CD3OD-d₄) δ 8.66 (d, J=8.0, 1H), 8.30 (t, J=8.8, 1H), 7.86 (s, 1H),7.35 (dd, J=7.6, 1.2, 2H); 7.31 (dd, J=12.0, 2.0, 1H), 7.24 (dd, J=8.4,1.2, 1H), 4.39 (s, 2H), 4.07 (s, 2H), 2.82 to 2.73 (m, 8H), 2.52 (s,3H), 1.94 (s, 3H); MS [M+H]⁺=605.0; LCMS RT=2.63.

Example 49 Preparation ofN-{4-[4-amino-6-(methoxymethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 26 was used to preparethe title compound by substituting Intermediate AR for Intermediate Q.¹H-NMR (CD3OD-d₄) δ 8.67 (d, J=2.4, 1H), 7.84 (s, 1H), 7.66 to 7.62 (m,3H), 7.44 to 7.41 (m, 2H); 7.32 (dd, J=8.0, 0.8, 1H), 4.41 (s, 2H), 4.01(s, 2H), 3.68 (t, J=4.4, 4H), 3.29 (s, 3H), 2.59 (t, J=4.4, 4H); MS[M+H]⁺=591.8; LCMS RT=2.63.

Example 50 Preparation ofN-{4-[4-amino-6-(methoxymethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[6-(trifluoro-methyl)pyridin-2-yl]urea

The procedure used for the preparation of Example 26 was used to preparethe title compound by substituting Intermediate AQ for Intermediate Q.¹H-NMR (DMSO-d₆) δ 10.14 to 10.05 (m, 1H), 9.93 to 9.88 (m, 1H), 8.04(t, J=9.2, 3H); 7.61 (d, J=8.0, 2H), 7.51 (dd, J=6.4, 1.6, 1H), 7.36 (d,J=8.8, 2H), 4.74 (s, 2H), 4.38 (s, 2H), 4.03 to 3.92 (m, 2H), 3.76 to3.66 (m, 2H), 3.52 to 3.41 (m, 2H), 3.38 to 3.28 (m, 2H), 3.22 (s, 3H);MS [M+H]⁺=556.8; LCMS RT=2.37.

Example 51 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)-6-(1,3-oxazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 26 was used to preparethe title compound by substituting Intermediate O for Intermediate Q.¹H-NMR (DMSO-d₆) δ 9.45 (s, 1H), 9.30 (s, 1H), 8.66 to 8.61 (m, 1H),8.32 to 8.24 (m, 2H), 7.97 (s, 1H), 7.54 to 7.47 (m, 1H), 7.43 to 7.37(m, 1H), 7.31 to 7.26 (m, 1H), 7.17 to 7.12 (m, 1H), 6.99 (s, 1H), 3.92(s, 2H), 3.53 to 3.47 (m, 4H), 2.43 to 2.36 (m, 4H); MS [M+H]⁺=615.0;LCMS RT=2.65.

Example 52 Preparation of4-amino-7-(morpholin-4-ylmethyl)-N-(2,2,2-trifluoroethyl)-5-{4-[({[6-(trifluoromethyl)pyridin-2-yl]amino}-carbonyl)-amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide

To a solution of morpholine (80.9 mg, 0.93 mmol) in acetic acid (1 mL)was added a 37% aqueous formaldehyde solution (0.07 mL, 0.93 mmol). Themixture was stirred at rt under nitrogen for 20 min and was added to asolution of Intermediate AP(4-amino-N-(2,2,2-trifluoroethyl)-5-{4-[({[6-(trifluoromethyl)pyridin-2-yl]amino}-carbonyl)-amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide(50.0 mg, 0.093 mmol)) in acetic acid (2 mL). The resultant solution washeated (60° C.) overnight and concentrated. The crude material wasdirectly purified by HPLC using a gradient of 35-40% MeCN in watercontaining 0.1% trifluoroacetic acid. The combined fractions wereconcentrated under reduced pressure. The residue was dissolved in EtOAc(15 mL). The organic layer was washed with a 2.0 M Na₂CO₃ aqueoussolution (15 mL), brine (15 mL), dried (Na₂SO₄) and concentrated underreduced pressure to yield 18.7 mg (32%) of the title compound. ¹H-NMR(DMSO-d₆) δ 10.0 (t, J=6.3 Hz, 1H), 9.89 (bs, 1H), 9.71 (bs, 1H),8.05-8.00 (m, 2H), 7.98 (s, 1H), 7.52-7.49 (m, 3H), 7.31 (d, J=8.6 Hz,2H), 4.12-3.98 (m, 4H), 3.56 (bs, 4H), 2.44 ((bs, 4H); MS [M+H]⁺=638.1;LCMS RT=2.92 min.

Example 53 Preparation of4-amino-7-[(dimethylamino)methyl]-N-(2,2,2-trifluoroethyl)-5-{-4-[({[6-(trifluoromethyl)-pyridin-2-yl]amino}carbonyl)-amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide

The procedure used for the preparation of Example 52 was used to preparethe title compound by substituting dimethylamine for morpholine. ¹H-NMR(DMSO-d₆) δ 10.24 (t, J=6.0 Hz, 1H), 9.92 (s, 1H), 9.73 (s, 1H),8.07-8.00 (m, 2H), 7.99 (s, 1H), 7.53-7.51 (m, 3H), 7.33 (d, J=8.6 Hz,2H), 4.08-4.02 (m, 2H), 3.95 (s, 2H), 2.23 (s, 6H); MS [M+H]⁺=595.8;LCMS RT=2.48 min.

Example 54 Preparation ofN-4-[4-amino-6-cyano-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Step 1: Preparation ofN-[4-(4-amino-7-bromo-6-cyanopyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a solution of acetonitrile (6.5 mL) was added Intermediate R(N-[4-(4-amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea)(300 mg, 0.659 mmol) followed by N-bromosuccinimide (129 mg, 0.725mmol). The solution was heated at 60° C. for 1 h. Upon cooling to rt thesolution was diluted with ethyl acetate (30 mL) and transferred to aseparatory funnel. The organic layer was washed with aq 1 N NaOH (20 mL)followed by water (20 mL). The organic was isolated, dried (MgSO₄),filtered, and concentrated to dryness. The crude material was thenpurified by flash column chromatography eluting with 95:5 v/vdichloromethane-methanol producing 267 mg (0.500 mmol, yield 76%) ofpurified solid. ¹H-NMR (DMSO-d₆) δ 9.41 (s, 1H), 8.99 (d, J=2.6 Hz, 1H),8.61 (dd, J=7.3, 2.3 Hz, 1H), 8.41 (br s, 1H), 8.11 (s, 1H), 7.65 (d,J=8.6 Hz, 2H), 7.50 (m, 1H), 7.45 (d, J=8.7 Hz, 2H), 7.39 (m, 1H), 5.87(br s, 1H); MS [M+H]⁺=534.0; LCMS RT=3.51.

Step 2: Preparation ofN-[4-(4-amino-6-cyano-7-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a solution of THF (20 mL) was addedN-[4-(4-amino-7-bromo-6-cyanopyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea(230 mg, 0.430 mmol) which was cooled to −77° C. n-BuLi (2.5 M inhexanes, 0.86 mL, 2.15 mmol) was slowly added to the solution viasyringe. The solution was stirred for 10 min and then DMF (0.20 mL, 2.58mmol) was added. The cooling bath was removed and the reaction wasallowed to warm to ambient temperature over the following 17 h. EtOAc(20 mL) and water (20 mL) were added to the reaction which was thentransferred to a separatory funnel. The organic layer was washed with aq1 N NaOH (20 mL) followed by water (20 mL). The organic was isolated,dried (MgSO₄), filtered, and concentrated to dryness yielding 207 mg(0.428 mmol, yield 99%) of product. ¹H-NMR (DMSO-d₆) δ 10.38 (s, 1H),9.43 (s, 1H), 8.99 (d, J=2.7 Hz, 1H), 8.68 (br s, 1H), 8.61 (dd, J=6.8,1.8 Hz, 1H), 8.27 (s, 1H), 7.66 (d, J=8.6 Hz, 2H), 7.52 (m, 1H), 7.47(d, J=8.6 Hz, 2H), 7.40 (m, 1H), 6.06 (br s, 1H); MS [M+H]⁺=484.1; LCMSRT=3.34.

Step 3: Preparation of the Title Compound

To a solution ofN-[4-(4-amino-6-cyano-7-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea(40.0 mg, 0.083 mmol) in THF (1.0 mL) was added AcOH (47 μL, 0.83 mmol)and morpholine (36 μL, 0.41 mmol). The reaction was heated at 60° C. for1 h after which sodium cyanoborohydride (26.0 mg, 0.41 mmol) was added.The reaction was heated at 60° C. for an additional 1 h. The reactionwas diluted with EtOAc, transferred to a separatory funnel and washedwith saturated aq NaHCO₃ (2×). The organic was dried (MgSO₄) andevaporated to give a crude oil that was purified by flash columnchromatography eluting with 5:4:1 v/v/v CH₂Cl₂-EtOAc-MeOH. The resultingpurified fractions were combined and evaporated producing 22 mg (0.039mmol, yield 48%) of the title compound as a white solid. ¹H-NMR(DMSO-d₆) δ 9.41 (s, 1H), 9.00 (d, J=2.9 Hz, 1H), 8.64 (dd, J=7.2, 2.3Hz, 1H), 8.27 (br s, 1H), 8.06 (s, 1H), 7.66 (m, 2H), 7.53 (m, 1H), 7.47(m, 2H), 7.41 (m, 1H), 5.72 (br s, 1H), 3.95 (s, 2H), 3.57 (m, 4H), 2.49(m, 4H); MS [M+H]⁺=555.0; LCMS RT=2.55.

Example 55N-(4-4-amino-6-cyano-7-[(4-methylpiperazin-1-yl)methyl]-pyrrolo[2,1-f][1,2,4]triazin-5-ylphenyl)-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

The procedure used for the preparation of Example 54, Step 3 was used toprepare the title compound by substituting 1-methylpiperazine formorpholine. ¹H-NMR (DMSO-d₆) δ 9.39 (s, 1H), 8.98 (d, J=3.0 Hz, 1H),8.62 (dd, J=6.8, 2.2 Hz, 1H), 8.23 (br s, 1H), 8.04 (s, 1H), 7.64 (m,2H), 7.51 (m, 1H), 7.45 (m, 2H), 7.40 (m, 1H), 5.71 (br s, 1H), 3.93 (s,2H), 2.49 (m, 4H), 2.33 (m, 4H), 2.14 (s, 3H); MS [M+H]⁺=568.1; LCMSRT=2.60.

Example 56N-[4-(4-amino-6-cyano-7-[(2,2,2-trifluoroethyl)-amino]methylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 54, Step 3 was used toprepare the title compound by substituting 2,2,2-trifluoroethanamine formorpholine. ¹H-NMR (DMSO-d₆) δ 9.49 (s, 1H), 9.02 (d, J=2.5 Hz, 1H),8.62 (dd, J=7.1, 2.3 Hz, 1H), 8.35 (br s, 1H), 8.08 (s, 1H), 7.65 (m,2H), 7.50 (m, 1H), 7.43 (m, 2H), 7.40 (m, 1H), 5.88 (br s, 1H), 4.26 (s,2H), 3.45 (br s, 2H); MS [M+H]⁺=567.2; LCMS RT=3.35.

Example 57N-4-[6-acetyl-4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f]-[1,2,4]triazin-5-yl]-2-fluorophenyl-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a solution of DCE (1 mL) was added Intermediate AX(1-[4-amino-5-(4-amino-3-fluorophenyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]-ethanone(40 mg, 0.10 mmol)) followed by1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene (32 μL, 0.22 mmol). Thereaction was heated at 80° C. for 17 h, and then aq 2 N HCl (52 μL, 0.10mmol) was added to the reaction followed by DMF (1 mL). The solution washeated for an additional 2.5 h. Upon cooling to rt, the solution wasconcentrated in vacuo and subsequently purified by MPLC (100% CH₂Cl₂ to5:4:1 v/v/v CH₂Cl₂-EtOAc-MeOH). The resulting purified fractions werecombined and evaporated producing 44 mg (0.075 mmol, yield 72%) of awhite solid. ¹H-NMR (DMSO-d₆) δ 9.48 (m, 1H), 9.34 (m, 1H), 8.67 (m,1H), 8.32 (t, J=8.4 Hz, 1H), 7.99 (s, 1H), 7.53 (m, 1H), 7.42 (m, 1H),7.38 (m, 1H), 7.20 (m, 1H), 4.07 (s, 2H), 3.50 (m, 4H), 2.42 (m, 4H),2.15 (s, 3H); MS [M+H]⁺=590.0; LCMS RT=2.62.

Example 58N-4-[6-acetyl-4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl-N′-[3-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 57 was used to preparethe title compound by substituting1-isocyanato-3-(trifluoromethyl)benzene for1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene. ¹H-NMR (DMSO-d₆) δ9.51 (s, 1H), 8.82 (m, 1H), 8.27 (t, J=8.7 Hz, 1H), 8.06 (s, 1H), 7.99(s, 1H), 7.56 (m, 2H), 7.37 (m, 2H), 7.19 (m, 1H), 4.07 (s, 2H), 3.50(m, 4H), 2.42 (m, 4H), 2.15 (s, 3H); MS [M+H]⁺=572.0; LCMS RT=2.67.

Example 59N-4-[6-acetyl-4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl-N′-[4-(trifluoromethoxy)phenyl]urea

The procedure used for the preparation of Example 57 was used to preparethe title compound by substituting1-isocyanato-4-(trifluoromethoxy)benzene for1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene. ¹H-NMR (DMSO-d₆) δ9.35 (s, 1H), 8.77 (m, 1H), 8.28 (t, J=8.7 Hz, 1H), 7.99 (s, 1H), 8.06(s, 1H), 7.58 (m, 2H), 7.36 (m, 1H), 7.32 (m, 2H), 7.19 (m, 1H), 4.07(s, 2H), 3.50 (m, 4H), 2.42 (m, 4H), 2.15 (s, 3H); MS [M+H]⁺=588.1; LCMSRT=3.04.

Example 60N-4-[6-acetyl-4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

To a solution of THF (0.2 mL) was added Intermediate AX(1-[4-amino-5-(4-amino-3-fluorophenyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]ethanone(43 mg, 0.11 mmol)) followed by Intermediate V(phenyl[4-(trifluoromethyl)pyridin-2-yl]carbamate (32 mg, 0.11 mmol))and triethylamine (16 μL, 0.11 mmol). The reaction was heated whilestirring at 50° C. for 4.5 h. The solution was concentrated in vacuo andsubsequently purified by MPLC (100% CH₂Cl₂ to 5:4:1 v/v/vCH₂Cl₂-EtOAc-MeOH). The resulting purified fractions were combined andevaporated producing 25 mg (0.043 mmol, yield 39%) of a white solid.¹H-NMR (DMSO-d₆) δ 10.19 (s, 1H), 10.15 (br s, 1H), 8.56 (d, J=5.4 Hz,1H), 8.32 (t, J=8.4 Hz, 1H), 8.02 (s, 1H), 7.99 (s, 1H), 7.41 (m, 1H),7.39 (m, 1H), 7.21 (m, 1H), 4.07 (s, 2H), 3.50 (m, 4H), 2.42 (m, 4H),2.15 (s, 3H); MS [M+H]⁺=573.0; LCMS RT=2.57.

Example 61N-4-[6-acetyl-4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl-N′-[6-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Example 60 was used to preparethe title compound by substitutingphenyl[6-(trifluoromethyl)pyridin-2-yl]carbamate forphenyl[4-(trifluoromethyl)pyridin-2-yl]carbamate. ¹H-NMR (DMSO-d₆) δ10.34 (s, 1H), 10.23 (br s, 1H), 8.35 (t, J=8.4 Hz, 1H), 8.05 (t, J=6.3Hz, 1H), 7.98 (s, 1H), 7.84 (d, J=8.7 Hz, 1H), 7.54 (d, J=7.4 Hz, 1H),7.39 (m, 1H), 7.20 (m, 1H), 4.06 (s, 2H), 3.49 (m, 4H), 2.41 (m, 4H),2.14 (s, 3H); MS [M+H]⁺=573.0; LCMS RT=2.50.

Example 62 Preparation ofN-{4-[4-amino-6-(hydroxymethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)-pyridin-2-yl]urea

A solution of formaldehyde (20 μL, 0.271 mmol, 37% in H₂O) andmorpholine (24 μL, 0.271 mmol) in AcOH (0.5 mL) was added to a stirringsolution of Intermediate Y (100 mg, 0.23 mmol) in AcOH (1.5 mL) at 60°C. The reaction was allowed to stir until all starting material had beenconsumed as shown by HPLC. The reaction mixture was quenched by dilutingwith EtOAc and washing 3× with saturated sodium carbonate solution. Theorganic layer was dried (Na₂SO₄) and concentrated to a brown powder. Thecrude product was purified by HPLC (10-70% ACN/H₂O) to yield 25.3 mg(0.5 mmol, 20.7%). ¹H-NMR (DMSO-d₆) δ 9.98 (s, 1H), 9.84 (s, 1H), 8.60(d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.95 (s, 1H), 7.69 (d, J=8.1 Hz, 2H),7.45-7.38 (m, 3H), 5.105 (s, 1H), 4.45 (s, 2H), 3.99 (s, 2H), 3.61-3.52(m, 4H), 2.55-2.44 (m, 4H). MS [M+H]⁺=543; LCMS RT=2.29 min.

Example 63N-{4-[4-amino-6-(cyanomethyl)-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)-pyridin-2-yl]urea

The procedure used to prepare Example 62 was used to prepare the titlecompound by substituting Intermediate AE for Intermediate Y. The crudeproduct was purified by HPLC (10-70% ACN/H₂O). ¹H-NMR (DMSO-d₆) δ 10.11(s, 1H), 9.95 (s, 1H), 8.59 (d, J=4.8 Hz, 1H), 8.15 (s, 1H), 7.98 (s,1H), 7.75 (d, J=8.4 Hz, 2H), 7.44-7.49 (m, 3H), 3.99 (s, 2H), 3.89 (s,2H), 3.65-3.60 (m, 4H), 2.50-2.43 (m, 4H). MS [M+Na]⁺=574; LCMS RT=2.46min.

Example 64N-(4-{4-amino-6-(cyanomethyl)-7-[(2,6-dimethylmorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[4-(trifluoromethyl)-pyridin-2-yl]urea

The procedure used to prepare Example 62 was used to prepare the titlecompound by substituting Intermediate AE for Intermediate Y and2,6-dimethylmorpholine for morpholine. The crude product was purified byHPLC (10-70% ACN/H₂O). ¹H-NMR (DMSO-d₆) δ 10.02 (s, 1H), 9.86 (s, 1H),8.60 (d, J=5.4 Hz, 1H), 8.12 (s, 1H), 7.97 (s, 1H), 7.73 (d, J=8.1 Hz,2H), 7.50-7.40 (m, 3H), 3.95 (s, 2H), 3.87 (s, 2H), 3.69-3.55 (m, 2H),2.74 (d, J=10.5 Hz, 4H), 1.06 (d, J=5.7 Hz, 6H). MS [M+H]⁺=580; LCMSRT=2.58 min.

Example 65N-{4-[7-[(4-acetylpiperazin-1-yl)methyl]-4-amino-6-(cyanomethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)-pyridin-2-yl]urea

The procedure used to prepare Example 62 was used to prepare the titlecompound by substituting Intermediate AE for Intermediate Y and1-acetylpiperazine for morpholine. The crude product was purified byHPLC (10-70% ACN/H₂O). ¹H-NMR (DMSO-d₆) δ 10.05 (s, 1H), 9.89 (s, 1H),8.60 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.98 (s, 1H), 7.74 (d, J=8.7 Hz,2H), 7.46-7.40 (m, 3H), 4.02 (s, 2H), 3.89 (s, 2H), 3.52-3.42 (m, 4H),2.52-2.45 (m, 2H), 2.45-2.40 (m, 2H), 2.02 (s, 3H). MS [M+Na]⁺=616; LCMSRT=2.37 min.

Example 66N-(4-{4-amino-6-(cyanomethyl)-7-[(3-oxopiperazin-1-yl)methyl]-pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used to prepare Example 62 was used to prepare the titlecompound by substituting Intermediate AE for Intermediate Y and2-oxopiperazine for morpholine. The crude product was purified by HPLC(10-70% ACN/H₂O). ¹H-NMR (DMSO-d₆) δ 10.06 (s, 1H), 9.90 (s, 1H),8.61-8.58 (m, 1H), 8.12 (s, 1H), 7.99 (s, 1H), 7.81-7.73 (m, 2H),7.48-7.40 (m, 3H), 4.73 (s, 2H), 4.04 (s, 2H), 3.91 (s, 2H), 3.20-3.12(m, 2H), 2.75-2.63 (m, 2H). MS [M+Na]⁺=587; LCMS RT=2.44 min.

Example 67N-[4-(4-amino-6-(cyanomethyl)-7-{[4-(methylsulfonyl)piperazin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used to prepare Example 62 was used to prepare the titlecompound by substituting Intermediate AE for Intermediate Y and1-methanesulfonylpiperaizne for morpholine. The crude product waspurified by HPLC (10-70% ACN/H₂O). ¹H-NMR (DMSO-d₆). δ 8.58 (d, J=5.1Hz, 1H), 8.14 (s, 1H), 7.98 (s, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.44-7.37(m, 3H), 4.05 (s, 2H), 3.89 (s, 2H), 3.20-3.11 (m, 4H), 2.89 (s, 3H),2.61-2.55 (m, 4H). MS [M+Na]⁺=651; LCMS RT=2.92 min.

Example 68N-{4-[4-amino-6-(cyanomethyl)-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

The procedure used to prepare Example 62 was used to prepare the titlecompound by substituting Intermediate AD for Intermediate Y. The crudeproduct was purified by HPLC (10-70% ACN/H₂O). ¹H-NMR (DMSO-d₆). δ 8.55(d, J=7.2 Hz, 1H), 7.97 (s, 1H), 7.79-7.73 (m, 3H), 7.55-7.37 (m, 3H),3.98 (s, 2H), 3.88 (s, 2H), 3.62-3.55 (m, 4H), 2.50-2.41 (m, 4 H). MS[M+H]⁺=569; LCMS RT=2.62 min.

Example 69N-{4-[4-amino-6-(cyanomethyl)-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used to prepare Example 62 was used to prepare the titlecompound by substituting Intermediate AC for Intermediate Y. The crudeproduct was purified by HPLC (10-70% ACN/H₂O). ¹H-NMR (DMSO-d₆). δ9.60-9.30 (br s, 2H), 8.71 (d, J=6.3 Hz, 1H), 8.39 (t, J=8.6 Hz, 1H),7.98 (s, 1H), 7.60-7.38 (m, 4H), 7.25 (d, J=7.5 Hz, 1H), 3.98 (s, 2H),3.93 (s, 2H), 3.75-3.45 (m, 4H), 2.50-2.41 (m, 4H). MS [M+H]⁺=587; LCMSRT=2.76 min.

Example 70 Preparation ofN-(4-{4-amino-6-(cyanomethyl)-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 62 was used to preparethe title compound by substituting Intermediate AD for Intermediate Yand by substituting 2-oxopiperazine for morpholine. ¹H-NMR (CD₃OD) δ8.62 (d, J=8.4 Hz, 1H), 8.04 (s, 1H), 7.72 (d, J=8.8 Hz, 2H), 7.45 (d,J=8.8 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 4.47 (s, 2H), 3.87 (s, 2H),3.48-3.44 (m, 4H), 3.15-3.09 (m, 2H); MS [M+H]⁺=582; LCMS RT=2.58.

Example 71 Preparation ofN-(4-{4-amino-6-(cyanomethyl)-7-[(2,6-dimethyl-morpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 62 was used to preparethe title compound by substituting Intermediate AD for Intermediate Yand by substituting 2,6-dimethylmorpholine for morpholine. ¹H-NMR(CD₃OD) δ 8.62 (d, J=7.6 Hz, 1H), 8.04 (s, 1H), 7.70 (d, J=8.4 Hz, 2H),7.44 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 4.85 (s, 2H), 3.91 (s,2H), 3.51 (d, J=11.6 Hz, 2H), 2.94 (t, J=11.6 Hz, 2H), 1.25 (d, J=6.4Hz, 6H); MS [M+H]⁺=597.2; LCMS RT=2.97.

Example 72 Preparation ofN-[4-(4-amino-6-(cyanomethyl)-7-{[2-(hydroxymethyl)morpholin-4-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 62 was used to preparethe title compound by substituting Intermediate AD for Intermediate Yand by substituting morpholin-2-ylmethanol for morpholine. ¹H-NMR(CD₃OD) δ 8.62 (d, J=7.2 Hz, 1H), 8.06 (s, 1H), 7.71 (d, J=8.8 Hz, 2H),7.44 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 4.16 (dd, J=12.8, 4.00Hz, 1H), 3.91 (s, 2H), 3.90-3.82 (m, 2H), 3.65 (s, 2H), 3.62-3.47 (m,4H), 3.26-3.18 (m, 2H); MS [M+H]⁺=599.1; LCMS RT=2.91.

Example 73 Preparation ofN-(4-{4-amino-6-(cyanomethyl)-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 62 was used to preparethe title compound by substituting Intermediate AD for Intermediate Yand by substituting thiomorpholine 1,1-dioxide for morpholine. ¹H-NMR(CD₃OD) δ 8.62 (d, J=7.2 Hz, 1H), 8.06 (s, 1H), 7.72 (d, J=8.8 Hz, 2H),7.45 (d, J=8.8 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 4.27 (s, 2H), 3.84 (s,2H), 3.20-3.15 (m, 4H), 3.13-3.06 (m, 4H); MS [M+H]⁺=617.2; LCMSRT=3.12.

Example 74 Preparation ofN-(4-{4-amino-6-(cyanomethyl)-7-[(4-methylpiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 62 was used to preparethe title compound by substituting Intermediate AD for Intermediate Yand by substituting N-methyl piperazine for morpholine. ¹H-NMR (CD₃OD) δ8.61 (d, J=8.0 Hz, 1H), 8.07 (s, 1H), 7.72 (d, J=8.8 Hz, 2H), 7.45 (d,J=8.8 Hz, 2H), 7.36 (d, J=8.8 Hz, 2H), 4.20 (s, 2H), 3.83 (s, 2H),3.48-3.32 (m, 2H), 3.30-3.16 (m, 4H), 2.90 (s, 3H), 2.88-2.80 (m, 2H);MS [M+H]⁺=582; LCMS RT=2.64.

Example 75 Preparation ofN-(4-{4-amino-6-(cyanomethyl)-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 62 was used to preparethe title compound by substituting Intermediate AD for Intermediate Yand by substituting piperazine for morpholine. ¹H-NMR (CD₃OD) δ 8.61 (d,J=8.8 Hz, 1H), 8.02 (s, 1H), 7.72 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.0 Hz,2H), 7.36 (d, J=8.0 Hz, 2H), 4.19 (s, 2H), 3.82 (s, 2H), 3.28 (t, J=6.0Hz, 4H), 2.81 (t, J=6.0 Hz, 4H); MS [M+H]⁺=568; LCMS RT=2.64.

Example 76 Preparation ofN-(4-{4-amino-6-(cyanomethyl)-7-[(4-isopropylsulfonylpiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 62 was used to preparethe title compound by substituting Intermediate AD for Intermediate Yand by substituting 1-(isopropylsulfonyl)piperazine for morpholine.¹H-NMR (CD₃OD) δ 8.62 (d, J=8.0 Hz, 1H), 8.04 (s, 1H), 7.71 (d, J=8.8Hz, 2H), 7.45 (d, J=8.8 Hz, 2H), 7.35 (d, J=6.8 Hz, 2H), 5.42 (s, 2H),4.09-3.90 (m, 3H), 3.91 (s, 2H), 3.79-3.62 (m, 4H), 3.35-3.32 (m, 2H),1.35 (d, J=6.8 Hz, 6H); MS [M+H]⁺=674; LCMS RT=2.98.

Example 77 Preparation of t-butyl4-[(4-amino-6-(cyanomethyl)-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)-amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl]piperazine-1-carboxylate

The procedure used for the preparation of Example 62 was used to preparethe title compound by substituting Intermediate AD for Intermediate Yand by substituting tert-butyl piperazine-1-carboxylate for morpholine.¹H-NMR (CD₃OD) δ 8.62 (d, J=8.0 Hz, 1H), 7.95 (s, 1H), 7.68 (d, J=8.8Hz, 2H), 7.44 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.8 Hz, 2H), 5.01 (s, 2H),4.07 (s, 2H), 4.01 (s, 2H), 3.66-3.63 (m, 4H), 3.31-3.29 (m, 2H), 1.47(s, 9H); MS [M+H]⁺=668.1; LCMS RT=3.09.

Example 78 Preparation ofN-(4-{4-amino-6-(cyanomethyl)-7-[(4-methylpiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}2-fluoro-phenyl)-N′[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 62 was used to preparethe title compound by substituting Intermediate AC for Intermediate Yand by substituting N-methyl piperazine for morpholine. ¹H-NMR (CD₃OD) δ8.64 (d, J=8.4 Hz, 1H), 8.42 (t, J=8.4 Hz, 1H), 8.08 (s, 1H), 7.37-7.27(m, 4H), 4.20 (s, 2H), 3.86 (s, 2H), 3.42-3.22 (m, 6H), 2.90 (s, 3H),2.88-2.75 (m, 2H); MS [M+H]⁺=600.1; LCMS RT=2.93.

Example 79 Preparation ofN-(4-{4-amino-6-(cyanomethyl)-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 62 was used to preparethe title compound by substituting Intermediate AC for Intermediate Yand by substituting thiomorpholine 1,1-dioxide for morpholine. ¹H-NMR(CD₃OD) δ 8.65 (d, J=6.4 Hz, 1H), 8.41 (t, J=8.4 Hz, 1H), 8.04 (s, 1H),7.37-7.26 (m, 4H), 4.26 (s, 2H), 3.86 (d, J=2.4 Hz, 2H), 3.20-3.15 (m,4H), 3.11-3.08 (m, 4H); MS [M+H]⁺=635.2; LCMS RT=3.19.

Example 80 Preparation ofN-(4-{4-amino-6-(cyanomethyl)-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 62 was used to preparethe title compound by substituting Intermediate AC for Intermediate Yand by substituting 2-oxopiperazine for morpholine. ¹H-NMR (CD₃OD) δ9.14 (d, J=2.4 Hz, 1H), 9.09 (d, J=2.8 Hz, 1H), 8.65 (d, J=6.8 Hz, 1H),8.43-8.37 (m, 1H), 8.04 (s, 1H), 7.37-7.25 (m, 4H), 4.45 (s, 2H), 3.89(s, 2H), 3.48 (s, 2H), 3.44 (t, J=4.8 Hz, 2H), 3.09 (t, J=4.8 Hz, 2H);MS [M+H]⁺=600; LCMS RT=3.01.

Example 81 Preparation ofN-(4-{4-amino-6-(cyanomethyl)-7-{[2-(hydroxymethyl)morpholin-4-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 62 was used to preparethe title compound by substituting Intermediate AC for Intermediate Yand by substituting morpholin-2-ylmethanol for morpholine. ¹H-NMR(CD₃OD) δ 8.65 (d, J=7.6 Hz, 1H), 8.41 (t, J=8.0 Hz, 1H), 8.08 (s, 1H),7.37-7.26 (m, 4H), 4.15 (dd, J=13.2, 2.4 Hz, 1H), 3.96 (s, 2H),3.92-3.84 (m, 2H), 3.64 (t, J=3.2 Hz, 2H), 3.60-3.50 (m, 2H), 3.38-3.19(m, 4H); MS [M+H]⁺=617; LCMS RT=2.96.

Example 82 Preparation ofN-(4-{4-amino-6-(cyanomethyl)-7-[(2,6-dimethylmorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 62 was used to preparethe title compound by substituting Intermediate AC for Intermediate Yand by substituting 2,6-dimethylmorpholine for morpholine. ¹H-NMR(CD₃OD) δ 8.67 (d, J=8.0 Hz, 1H), 8.41 (t, J=8.0 Hz, 1H), 8.06 (s, 1H),7.37-7.26 (m, 4H), 4.85 (s, 2H), 3.94 (s, 2H), 3.91-3.88 (m, 2H), 3.52(d, J=12.0 Hz, 2H), 2.93 (d, J=12.0 Hz, 2H), 1.24 (d, J=6.4 Hz, 6H); MS[M+H]⁺=615.1; LCMS RT=3.08.

Example 83 Preparation ofN-(4-{4-amino-6-(cyanomethyl)-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 62 was used to preparethe title compound by substituting Intermediate AS for Intermediate Yand by substituting thiomorpholine 1,1-dioxide for morpholine. ¹H-NMR(CD₃OD) δ 9.53 (s, 1H), 8.95 (s, 1H), 8.66 (s, 1H), 8.43-8.38 (m, 1H),8.06 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.35-7.24 (m, 3H), 4.26 (s, 2H),3.87 (m, 4H), 3.96 (d, J=2.8 Hz, 2H), 3.20-3.17 (m, 4H), 3.12-3.09 (m,4H); MS [M+H]⁺=650.9; LCMS RT=3.04.

Example 84 Preparation ofN-(4-{4-amino-6-(cyanomethyl)-7-[(morpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 62 was used to preparethe title compound by substituting Intermediate AS for Intermediate Y.¹H-NMR (CD₃OD) δ 9.52 (s, 1H), 8.95 (s, 1H), 8.66 (s, 1H), 8.42-8.38 (m,1H), 8.06 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.35-7.24 (m, 3H), 4.90 (s,2H), 4.02-3.85 (m, 4H), 3.96 (s, 2H), 3.48-3.44 (m, 4H); MS[M+H]⁺=602.8; LCMS RT=2.68.

Example 85 Preparation ofN-{4-[4-amino-6-formyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoro-methyl)pyridin-2-yl]urea

Dess-Martin periodinane (703.6 mg, 1.66 mmol) was added to a stirringsolution of Example 62 (600 mg, 1.11 mmol) dissolved in DMSO (3 mL).After 1 hour HPLC indicated that the reaction was complete. The reactionwas diluted with EtOAc (200 mL) washed with aq. Sodium thiosulfatesolution (2M) (2×), and saturated NaHCO₃ solution (2×). The organiclayer was dried (Na₂SO₄) and concentrated to give a brown powder whichwas triturated with 10% Et₂O/Hexanes to afford 450 mg (0.83 mmol, 75.3%)of the title compound. ¹H-NMR (DMSO-d₆). δ 10.00 (s, 1H), 9.95 (s, 1H),9.84 (s, 1H), 8.60 (d, J=5.4 Hz, 1H), 8.12 (s, 1H), 8.07 (s, 1H), 7.89(d, J=8.7 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.43 (d, J=5.1 Hz, 1H), 4.18(s, 2H), 3.57-3.54 (m, 4H), 2.55-2.51 MS [M+H]⁺=541; LCMS RT=2.50 min.

Example 86N-{4-[4-amino-6-isobutyryl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)-pyridin-2-yl]urea

Step 1: Preparation ofN-{4-[4-amino-6-(1-hydroxy-1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

Methylmagnesium bromide (2.75 mL, 8.24 mmol, 3.0 M in Et₂O) was addeddrop wise to a stirring solution of Intermediate W (200 mg, 0.412 mmol)in THF (5 mL) at rt. The solution was heated to 60° C. for 2 h, afterwhich TLC indicated the reaction was complete. The reaction was quenchedwith EtOAc and washed with saturated NH₄Cl solution (3×). The organiclayer was dried (Na₂SO₄) and concentrated to a solid which wastriturated with Et₂O to give an off-white powder which was used directlyin the next step.

Step 2: Preparation of the Title Compound

The procedure used to prepare Example 62 was used to prepare the titlecompound by substitutingN-{4-[4-amino-6-(1-hydroxy-1-methylethyl)pyrrolo[2,1-f]-[1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]ureafor Intermediate Y. The crude product was purified by recrystallizationin acetonitrile. ¹H-NMR (DMSO-d₆). δ 8.55 (d, J=4.8 Hz, 1H), 8.27 (s,1H), 7.89 (s, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.34-7.31 (m, 3H), 6.82 (s,1H), 4.16 (s, 2H), 3.65-3.58 (m, 4H), 2.60-2.41 (m, 4H), 1.72 (s, 3H),1.29 (s, 3H). MS [M+H]⁺=571; LCMS RT=2.49 min.

Example 87N-{4-[4-amino-6-(difluoromethyl)-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)-pyridin-2-yl]urea

Deoxo-Fluor™ (0.38 mL, 0.740 mmol) was added to a stirring solution ofExample(N-{4-[4-amino-6-formyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f]-[1,2,4]triazin-5-yl]-phenyl}-N′-[4-(trifluoro-methyl)pyridin-2-yl]urea)(200 mg, 0.37 mmol) in THF (3 mL). The reaction mixture was stirreduntil no starting material remained by HPLC (5 minutes). The reactionwas diluted with EtOAc (150 mL) and washed with NaHCO₃ (3×). The organiclayer was dried (Na₂SO₄) and concentrated to give a brown powder whichwas purified by HPLC (10-70% ACN/H₂O) to yield 21.1 mg (0.04 mmol,10.1%). ¹H-NMR (DMSO-d₆). δ 10.1-9.8 (s, 2H, br), 8.60 (d, J=5.1 Hz,1H), 8.13 (s, 1H), 7.68 (d, J=9 Hz, 2H), 7.46-7.40 (m, 3H), 7.18 (t,J=54 Hz, 1H), 4.03 (s, 2H), 3.60-3.57 (m, 4H), 2.49-2.46 (m, 4H), MS[M+H]⁺=563; LCMS RT=2.94 min.

Example 88N-{4-[6-acetyl-4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)-pyridin-2-yl]urea

Step 1: Preparation ofN-{4-[4-amino-6-(1-hydroxyethyl)pyrrolo[2,1-f][1,2,4]-triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

A solution of Intermediate AF (60 mg, 0.136 mmol) in 5 mL THE wastreated with methylmagnesium bromide (0.68 mL, 2.1 mmol, 3 M in Et₂O)dropwise over 2 min. The reaction was allowed to stir for 15 min, thenquenched with MeOH, diluted with EtOAc and washed with aq. NH₄Cl. Theorganic layer was dried with sodium sulfate and evaporated to dryness.The residue was triturated with Et₂O to provide 50.1 mg of the titlecompound (82% yield). ¹H-NMR (DMSO) δ10.05 (s, 1H), 9.82 (s, 1H), 8.52(d, J=5 Hz, 1H), 8.09 (s, 1H), 7.81 (s, 1H), 7.64 (s, 1H), 7.61 (d, J=9Hz, 2H), 7.34 (d, J=9 Hz, 2H), 4.96 (d, J=5 Hz, 1 H), 4.63 (dq, J=5, 6Hz, 1H), 1.24 (d, J=6 Hz, 3H); MS [M+H]⁺=458.0; LCMS RT=2.41.

Step 2: Preparation ofN-{4-[4-amino-6-(1-hydroxyethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)-pyridin-2-yl]urea

The procedure used to prepare Example 62 was used to prepare the abovecompound by substitutingN-{4-[4-amino-6-(1-hydroxyethyl)pyrrolo[2,1f][1,2,4]-triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]ureafor Intermediate Y. The crude product was used directly in the nextstep. ¹H-NMR (DMSO-d₆). δ 9.97 (s, 1H), 9.82 (s, 1H), 8.59 (d, J=5.1 Hz,1H), 8.13 (s, 1H), 7.88 (s, 1H), 7.67 (d, J=9 Hz, 2H), 7.45-7.41 (m,3H), 5.03 (d, J=4.8 Hz, 1H), 4.74-4.68 (m, 1H), 1.31 (d, J=6.0 Hz, 3H).MS [M+H]⁺=557; LCMS RT=2.70 min.

Step 3: Preparation of the Title Compound

Dess-Martin periodinane (342.9 mg, 0.809 mmol) was added to a stirringsolution ofN-{4-[4-amino-6-(1-hydroxyethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]-triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)-pyridin-2-yl]urea(300 mg, 0.54 mmol) in DMSO (3 mL). The reaction was allowed to stiruntil complete by HPLC. Saturated aq. NaHCO₃ solution (0.25 volumes) wasadded until a lot of solid had crashed out. Then 2 volumes of EtOAc and0.5 volumes of H₂O was added. This was allowed to stir overnight and thenext day the excess liquid was removed via pipette. Careful addition of5-10 mL of Et₂O and 2 mL of CH₂Cl₂ provided an off white suspension.This was filtered to give a the title compound (100 mg, 0.18 mmol, 31%yield, 2 steps) as pure white powder. ¹H-NMR (DMSO-d₆). δ 10.20 (s, 1H),10.04 (s, 1H), 8.67 (d, J=5.1 Hz, 1H), 8.20 (s, 1H), 8.10 (s, 1H), 7.78(d, J=8.7 Hz, 2H), 7.52-7.48 (m, 3H), 4.19 (s, 2H), 3.63-3.60 (m, 4H),2.56-2.53 (m, 4H), 2.19 (s, 3H). MS [M+H]⁺=555; LCMS RT=2.51 min.

Example 89N-{4-[4-amino-6-(cyclopropylcarbonyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

Cyclopropyl magnesium bromide (7.40 mL, 3.70 mmol, 0.5 M in diethylether) was added dropwise to a stirring solution of Example 85 (200 mg,0.37 mmol) in THF (10 mL). This was allowed to stir until the reactionwas complete by HPLC (1 hour). Additional amounts of the grinard reagentwere added as needed. The reaction was quenched with methanol and wasworked up by adding 1 volume of saturated NH₄Cl solution and 5 volumesof EtOAc. The organic layer was washed 2× with NH₄Cl and 1× with sodiumcarbonate soln. The organic layer was dried over Na₂SO₄ andconcentrated. The crude intermediate was dissolved in DMSO (3 nth) andtreated with Dess-Martin periodinane (174.7 mg, 0.412 mmol). Thereaction was allowed to stir until the reaction was complete by HPLC (2hours). The reaction was diluted with EtOAc (200 mL) and washed 2× withboth saturated NaHCO₃ and 2M sodium thiosulfate solution. The organiclayer was dried over Na₂SO₄ and concentrated to give a crude solid whichwas purified by HPLC (10-70% ACN/H₂O) to give 26.3 mg of the abovecompound (0.04 mmol, 12.3% yield). ¹H-NMR (DMSO-d₆). δ 9.98 (s, 1H),9.82 (s, 1H), 8.60 (d, J=5.4 Hz, 1H), 8.11 (s, 1H), 8.03 (s, 1H), 7.69(d, J=8.4 Hz, 2H), 7.45-7.41 (m, 3H), 4.08 (s, 2H), 3.55-3.52 (m, 4H),2.46-2.43 (m, 4 H), 2.07-1.97 (m, 1H), 0.95-0.91 (m, 2H), 0.74-0.69 (m,2H). MS [M+H]⁺=581; LCMS RT=2.68 min.

Example 90N-{4-[4-amino-7-(morpholin-4-ylmethyl)-6-propionylpyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)-pyridin-2-yl]urea

The procedure used to prepare Example 89 was used to prepare the titlecompound by substituting ethyl magnesium bromide (3.0 M in diethylether) for cyclopropyl magnesium bromide. The crude product was purifiedby recrystallizing it in acetonitrile. ¹H-NMR (DMSO-d₆). δ 10.00 (s,1H), 9.84 (s, 1H), 8.60 (d, J=5.4 Hz, 1H), 8.12 (s, 1H), 8.02 (s, 1H),7.69 (d, J=9.0 Hz, 2H), 7.43-7.40 (m, 3H), 4.08 (s, 2H), 3.55-3.52 (m,4H), 2.53-2.41 (m, 6H), 0.91 (t, J=7.4 Hz, 3H). MS [M+H]⁺=569; LCMSRT=2.56 min.

Example 91N-{4-[4-amino-6-isobutyryl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)-pyridin-2-yl]urea

The procedure used to prepare Example 89 was used to prepare the titlecompound by substituting isopropyl magnesium bromide (2.0M in diethylether) for cyclopropyl magnesium bromide. The crude product was purifiedby HPLC (10-70% ACN/H₂O). ¹H-NMR (DMSO-d₆). δ 10.10-9.80 (s, 2H, br),8.59 (d, J=5.1 Hz, 1H), 8.12 (s, 1H), 8.02 (s, 1H), 7.69 (d, J=8.7 Hz,2H), 7.42-7.39 (m, 3H), 4.02 (s, 2H), 3.58-3.49 (m, 4H), 2.72-2.61 (m,1H), 2.49-2.35 (m, 4H), 0.91 (d, J=7.2 Hz, 6H). MS [M+H]⁺=583; LCMSRT=2.75 min.

Example 92N-{4-[4-amino-6-(2,2-dimethylpropanoyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)-pyridin-2-yl]urea

The procedure used to prepare Example 89 was used to prepare the titlecompound by substituting tert-butyl magnesium chloride (2.0 M in diethylether) for cyclopropyl magnesium bromide. The crude product was purifiedby HPLC (10-70% ACN/H₂O). ¹H-NMR (DMSO-d₆). δ 10.00-9.78 (s, 2H, br),8.59 (d, J=5.4 Hz, 1H), 8.11 (s, 1H), 8.00 (s, 1H), 7.65 (d, J=8.4, 2H),7.56 (d, J=5.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 2H), 3.82 (s, 2H), 3.59-3.51(m, 4H), 2.49-2.38 (m, 4H), 0.87 (s, 9H). MS [M+H]⁺=597; LCMS RT=2.83min.

Example 93N-(4-{6-acetyl-4-amino-7-[(2,6-dimethylmorpholin-4-yl)methyl]-pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Step 1: Preparation ofN-{4-[4-amino-6-(1-hydroxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

Intermediate N (100 mg, 0.20 mmol) in THF (5 mL) was added to a stirringsolution of methylmagnesium bromide (0.80 mL, 2.38 mmol, 3.0 M in Et₂O)in THF (10 mL) at 0° C. The reaction was allowed to warm to rt and stiruntil complete as seen by TLC (1 h). The reaction was quenched withmethanol (1 mL) and diluted with 5 volumes of EtOAc, an equal amount ofsaturated aq. NH₄Cl solution, and 1 volume of H₂O. The organic layer wasdried (Na₉SO₄) and concentrated to give a off-white solid (80 mg, 0.17mmol, 81% yield).

Step 2: Preparation ofN-{4-[4-amino-7-[(2,6-dimethylmorpholin-4-yl)methyl]-6-(1-hydroxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used to prepare Example 62 was used to prepare the abovecompound by substitutingN-{4-[4-amino-6-(1-hydroxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]ureafor Intermediate Y and 2,6-dimethylmorpholine for morpholine. The crudeproduct was used directly in the next reaction. MS [M+H]⁺=620; LCMSRT=2.72 min.

Step 3: Preparation of Title Compound

The procedure used to prepare Example 88, step 3 was used to prepare thetitle compound by substitutingN-{4-[4-amino-7-[(2,6-dimethylmorpholin-4-yl)methyl]-6-(1-hydroxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]ureaforN-{4-[4-amino-6-(1-hydroxyethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoro-methyl)-pyridin-2-yl]urea.¹H-NMR (DMSO-d₆). δ 9.51 (s, 1H), 9.38 (s, 1H), 8.71 (d, J=7.5 Hz, 1H),8.36 (t, J=8.7 Hz, 1H), 8.03 (s, 1H), 7.61-7.53 (m, 1H), 7.50-7.39 (m,2H), 7.24 (d, J=8.1 Hz, 1H), 4.08 (s, 2H), 2.70 (d, J=10.2, 2H), 2.19(s, 3H), 1.83 (t, J=10.5 Hz, 2H), 1.10 (d, J=6.3 Hz, 2H), 1.01 (d,J=11.4 Hz, 6H). MS [M+H]⁺=618; LCMS RT=2.76 min.

Example 944-amino-N-methoxy-N-methyl-7-[(4-methylpiperazin-1-yl)methyl]-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}-carbonyl)amino]-phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide

Step 1: Preparation of4-amino-N-methoxy-N-methyl-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide

Intermediate X (1235 mg, 2.70 mmol), triethylamine (1.04 mL, 7.53 mmol),and Benzotriazol-1-yloxytris(dimethylamino)-phosphoniumhexafluoro-phosphate (BOP, 1220 mg, 2.76 mmol) was combined along withDMF (20 mL). The mixture was allowed to stir until complete by HPLC (1hour). The reaction mixture was diluted with 5 volumes of EtOAc andwashed with pH 7 buffer, brine, and copious amounts of H₂O. The organiclayer was dried (Na₂SO₄) and concentrated to give an off-white powder(953 mg, 77% yield).

Step 2: Preparation of the Title Compound

A solution of formaldehyde (0.22 mL, 3.0 mmol, 37% in H₂O) and1-methylpiperazine (0.33 mL, 3.0 mmol) in AcOH (0.5 mL) was added to astirring solution of4-amino-N-methoxy-N-methyl-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}-carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide(150 mg, 0.30 mmol) in AcOH (1.5 mL) at 80° C. The reaction was allowedto stir overnight until all starting material had been consumed as shownby HPLC (15 hrs). The reaction mixture was worked up by diluting withEtOAc and washing 1× with saturated sodium carbonate solution, 1× withsaturated sodium bicarbonate solution, and 1× with brine. The organiclayer was dried over Na₂SO₄ and concentrated to a brown powder. Thecrude product was purified by HPLC (10-70% ACN/H₂O) to yield 100 mg(0.16 mmol, 54.5%) of the title compound. ¹H-NMR (DMSO-d₆). δ 10.02 (s,1H), 9.89 (s, 1H), 8.59 (d, J=5.4 Hz, 1H), 8.14 (s, 1H), 8.06 (s, 1H),7.67 (d, J=8.4 Hz, 2H), 7.42-7.37 (m, 3H), 3.87 (s, 2H), 2.51-2.38 (m,4H), 2.35-2.20 (m, 4H), 2.14 (s, 3H). MS [M+H]⁺=613; LCMS RT=2.37 min.

Example 95N-[4-(6-acetyl-4-amino-7-{[4-(methylsulfonyl)piperazin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Step 1: Preparation ofN-[4-(4-amino-6-(1-hydroxyethyl)-7-{[4-(methylsulfonyl)piperazin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used to prepare Example 62 was used to prepare the titlecompound by substituting the product of step 1 in Example 93(N-{4-[4-amino-6-(1-hydroxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea)for Intermediate Y and 1-methanesulfonylpiperazine for2,6-dimethylmorpholine. The crude product was used directly in the nextreaction. MS [M+H]⁺=669; LCMS RT=2.68 min.

Step 2: Preparation of Title Compound

The procedure used to prepare Example 88, step 3 was used to prepare thetitle compound by substitutingN-[4-(4-amino-6-(1-hydroxyethyl)-7-{[4-(methylsulfonyl)piperazin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluoro-phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]ureaforN-{4-[4-amino-6-(1-hydroxyethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoro-methyl)-Pyridin-2-yl]urea.¹H-NMR (DMSO-d₆). δ 8.70 (dd, J=1.8, 7.5 Hz, 1H), 8.36 (t, J=8.4 Hz,1H), 8.04 (s, 1H), 7.57-7.53 (m, 1H), 7.47-7.39 (m, 2H), 7.24 (dd,J=1.8, 8.4 Hz, 1H), 4.18 (s, 2H), 3.13-3.05 (m, 4H), 2.88 (s, 3H),2.62-2.55 (m, 4H). MS [M+H]⁺=667; LCMS RT=2.79 min.

Example 96N-(4-{6-acetyl-4-amino-7-[(4-methylpiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[4-(trifluoromethyl)-pyridin-2-yl]urea

Methyl magnesium bromide (0.54 mL, 1.63 mmol, in 3.0 M in diethyl ether)was added dropwise to a stirring solution of Example 94 (100.0 mg, 0.163mmol) in THF (2 mL) at rt. The reaction was heated to 60° C. and allowedto stir overnight (15 hrs) or until all starting material had beenconsumed as seen by HPLC. After cooling to rt, the reaction was quenchedwith methanol and diluted with 100 mL of EtOAc and washed 3× withsaturated NH₄Cl solution. The organic layer was dried over Na₂SO₄,concentrated and purified by HPLC (10-70% ACN/H₂O) to give 37.9 mg (0.07mmol, 40.9%) of the title compound. ¹H-NMR (DMSO-d₆). δ 10.88 (s, 1H),10.19 (s, 1H), 8.57 (d, J=5.4 Hz, 1H), 8.27 (s, 1H), 8.03 (s, 1H), 7.70(d, J=8.1 Hz, 2H), 7.40-7.35 (m, 3H), 4.17 (s, 2H), 3.08-3.04 (m, 4H),2.73-2.65 (m, 7H), 2.06 (s, 3H). MS [M+H]⁺=568; LCMS RT=2.31 min.

Example 974-amino-N-methoxy-N-methyl-7-(morpholin-4-ylmethyl)-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)-amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide

The procedure used to prepare Example 94 was used to prepare the titlecompound by substituting morpholine for 1-methylpiperazine. ¹H-NMR(DMSO-d₆). δ 8.58 (d, J=5.1 Hz, 1H), 8.17 (s, 1H), 7.72-7.66 (m, 2 H),7.60-7.45 (m, 1H), 7.43-7.36 (m, 3H), 3.88 (s, 2H), 3.61-3.50 (m, 7H),3.49-3.40 (s, 3H), 2.50-2.38 (m, 4H). MS [M+H]⁺=600; LCMS RT=2.47 min.

Example 98N-(4-{6-acetyl-4-amino-7-[(2,6-dimethylmorpholin-4-yl)methyl]-pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

Step 1: Preparation of4-amino-7-[(2,6-dimethylmorpholin-4-yl)methyl]-N-methoxy-N-methyl-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)-amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide

The procedure used to prepare Example 94 was used to prepare the abovecompound by substituting 2,6-dimethlylmorpholine for 1-methylpiperazine.The crude product was used directly in the next reaction. MS [M+H]⁺=628;LCMS RT=2.73 min.

Step 2: Preparation of Title Compound

The procedure used to prepare Example 96 was used to prepare the titlecompound by substituting4-amino-7-[(2,6-dimethylmorpholin-4-yl)methyl]-N-methoxy-N-methyl-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)-amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxamidefor Example 94. ¹H-NMR (Acetone-d₆). δ 8.47 (d, J=5.4 Hz, 1H), 7.78 (s,1H), 7.77 (s, 1H), 7.68 (d, J=10.8 Hz, 2H), 7.33 (d, J=8.7 Hz, 2H), 7.21(d, J=6.3 Hz, 1H), 4.02 (s, 2H), 2.61 (d, J=9.9 Hz, 2H), 1.71 (t, J=10.5Hz, 2H), 0.91 (d, J=6.9 Hz, 2H), 0.90 (d, J=6.3 Hz, 6H). MS [M+H]⁺=583;LCMS RT=2.65 min.

Example 99N-{4-[4-amino-6-(difluoromethyl)-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Step 1: Preparation ofN-{4-[4-amino-6-formyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used to prepare Example 94, step 2 was used to prepare theabove compound by substituting morpholine for 1-methylpiperazine andIntermediate N for the product of Step 1, Example 94(4-amino-N-methoxy-N-methyl-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]-triazine-6-carboxamide).The crude product was used directly in the next reaction. MS [M+H]⁺=576;LCMS RT=2.82 min.

Step 2: Preparation of the Title Compound

The procedure used to prepare Example 87 was used to prepare the titlecompound by substitutingN-{4-[4-amino-6-formyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]ureafor Example 85. ¹H-NMR (DMSO-d₆). δ 8.70 (dd, J=2.1, 7.2 Hz, 1H), 8.32(t, J=8.4 Hz, 1H), 8.03 (s, 1H), 7.56-7.46 (m, 1H), 7.50-7.32 (m, 2H),7.30-7.21 (m, 3H), 4.05 (s, 2H), 3.60-3.56 (m, 4H), 2.50-2.45 (m, 4H).MS [M+H]⁺=598; LCMS RT=3.07 min.

Example 100N-4-[4-amino-6-formyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 85 was used to preparethe title compound by Example 34 for Example 62. ¹H-NMR (DMSO-d₆) δ 9.91(s, 1H), 9.39 (s, 1H), 8.99 (d, J=2.8 Hz, 1H), 8.64 (dd, J=7.5, 2.0 Hz,1H), 8.03 (s, 1H), 7.61 (m, 2H), 7.52 (m, 1H), 7.44 (m, 2H), 7.41 (m,1H), 4.14 (s, 2H), 3.52 (m, 4H), 2.48 (m, 4H); MS [M+H]⁺=558.0; LCMSRT=2.68.

Example 101N-{4-[4-amino-6-(difluoromethyl)-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used to prepare Example 87 was used to prepare the titlecompound by substituting Example 100 for Example 85. ¹H-NMR (DMSO-d₆). δ8.67 (dd, J=2.1, 7.5 Hz, 1H), 8.02 (s, 1H), 7.64 (d, J=8.4 Hz, 2H),7.57-7.51 (m, 1H), 7.45-7.35 (m, 3H), 7.18 (t, J=54 Hz, 1H), 4.03 (s,2H), 3.61-3.56 (m, 4H), 2.50-2.45 (m, 4H). MS [M+H]⁺=580; LCMS RT=2.69min.

Example 102N-4-[4-amino-6-[(E)-(hydroxyimino)methyl]-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a solution of pyridine (10 mL) was added the product of Example 100(2.40 g, 4.31 mmol) followed by hydroxylamine hydrochloride (0.33 g,4.74 mmol). The reaction was stirred at ambient temperature for 3 h, andthen acetic anhydride (0.89 mL, 9.47 mmol) was added. The solution washeated at 80° C. for 2 h. Upon cooling to rt, the solution wasconcentrated in vacuo and subsequently purified by MPLC (Isco) 100%CH₂Cl₂ ramping to 9:1 v/v CH₂Cl₂-MeOH. The resulting purified fractionswere combined and evaporated producing 200 mg (0.349 mmol, yield 8%) ofa white solid. ¹H-NMR (DMSO-d₆) δ 10.98 (s, 1H), 9.37 (s, 1H), 8.99 (d,J=2.9 Hz, 1H), 8.64 (dd, J=7.6, 2.1 Hz, 1H), 7.95 (s, 2H), 7.60 (m, 2H),7.51 (m, 1H), 7.41 (m, 1H), 7.34 (m, 2H), 4.06 (s, 2H), 3.52 (m, 4H),2.48 (m, 4H); MS [M+H]⁺=572.9; LCMS RT=2.66.

Example 103N-4-[6-(E)-[(acetyloxy)imino]methyl-4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a solution of pyridine (10 mL) was added Example 100 (2.40 g, 4.31mmol) followed by hydroxylamine hydrochloride (0.33 g, 4.74 mmol). Thereaction was stirred at ambient temperature for 3 h, and then aceticanhydride (0.89 mL, 9.47 mmol) was added. The solution was heated at 80°C. for 2 h. Upon cooling to rt, the solution was concentrated in vacuoand subsequently purified by MPLC (Isco) 100% CH₂Cl₂ ramping to 9:1 v/vCH₂Cl₂-MeOH. The resulting purified fractions were combined andevaporated producing 700 mg (1.14 mmol, yield 27%) of a white solid.¹H-NMR (DMSO-d₆) δ 9.39 (s, 1H), 9.00 (d, J=2.9 Hz, 1H), 8.64 (dd,J=7.4, 2.6 Hz, 1H), 8.29 (s, 1H), 8.00 (s, 1H), 7.62 (m, 2H), 7.52 (m,1H), 7.42 (m, 1H), 7.38 (m, 2H), 4.12 (s, 2H), 3.51 (m, 4H), 2.53 (m,4H), 2.07 (s, 3H); MS [M+H]⁺=615.1; LCMS RT=2.80.

Example 104N-4-[4-amino-6-(1-hydroxyethyl)-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

The procedure used to prepare Example 89 (Grignard addition only-nooxidation) was used to prepare the title compound by substituting methylmagnesium bromide (3.0 M in diethyl ether) for cyclopropyl magnesiumbromide and by substituting Example 100 for Example 85. ¹H-NMR (DMSO-d₆)δ 9.35 (s, 1H), 8.98 (d, J=2.9 Hz, 1H), 8.64 (dd, J=7.1, 2.1 Hz, 1H),7.89 (s, 1H), 7.60 (m, 2H), 7.52 (m, 1H), 7.41 (m, 1H), 7.32 (m, 2H),5.90 (d, J=6.3 Hz, 1H), 4.69 (m, 1H), 4.13 (d, J=13.3 Hz, 1H), 3.94 (d,J=13.4 Hz, 1H), 3.53 (m, 4H), 2.44 (m, 4H), 1.36 (d, J=6.6 Hz, 3H); MS[M+H]⁺=574.1; LCMS RT=2.91.

Example 105N-4-[6-acetyl-4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used to prepare Example 85 was used to prepare the titlecompound by substituting Example 105 for Example 62. ¹H-NMR (DMSO-d₆) δ9.39 (s, 1H), 8.99 (d, J=2.9 Hz, 1H), 8.63 (dd, J=7.3, 2.4 Hz, 1H), 7.98(s, 1H), 7.62 (m, 2H), 7.52 (m, 1H), 7.42 (m, 1H), 7.38 (m, 2H), 4.07(s, 2H), 3.50 (m, 4H), 2.43 (m, 4H), 2.08 (s, 3H); MS [M+H]⁺=572.0; LCMSRT=2.70.

Example 106N-4-[4-amino-6-[cyclopropyl(hydroxy)methyl]-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used to prepare Example 89 (Grignard addition only-nooxidation) was used to prepare the title compound by substitutingExample 100 for Example 85. ¹H-NMR (DMSO-d₆) δ 9.36 (s, 1H), 9.00 (d,J=2.1 Hz, 1H), 8.64 (dd, J=7.5, 2.4 Hz, 1H), 7.90 (s, 1H), 7.59 (m, 2H),7.52 (m, 1H), 7.41 (m, 1H), 7.33 (m, 2H), 5.95 (d, J=7.0 Hz, 1H), 4.11(d, J=13.1 Hz, 1H), 3.98 (d, J=13.1 Hz, 1H), 3.83 (t, J=7.1 Hz, 1H),3.53 (m, 4H), 2.40 (m, 4H), 0.86 (m, 1H), 0.43 (m, 1H), 0.23 (m, 2H),−0.09 (m, 1H); MS [M+H]⁺=600.1; LCMS RT=2.95.

Example 107N-4-[4-amino-6-(cyclopropylcarbonyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used to prepare Example 85 was used to prepare the titlecompound by substituting Example 106 for Example 62. ¹H-NMR (DMSO-d₆) δ9.37 (s, 1H), 8.98 (d, J=2.5 Hz, 1H), 8.63 (dd, J=7.2, 2.2 Hz, 1H), 7.99(s, 1H), 7.60 (m, 2H), 7.52 (m, 1H), 7.41 (m, 1H), 7.37 (m, 2H), 4.04(s, 2H), 3.49 (m, 4H), 2.41 (m, 4H), 1.96 (m, 1H), 0.89 (m, 2H), 0.68(m, 2H); MS [M+H]⁺=598.1; LCMS RT=3.07.

Example 108N-4-[4-amino-6-[(2-methoxyethyl)amino]methyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a solution of Example 100(N-4-[4-amino-6-formyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea(50.0 mg, 0.090 mmol)) in THF (1.0 mL) was added AcOH (51 μL, 0.90 mmol)and 2-methoxyethanamine (39 μL, 0.45 mmol). The reaction was heated at60° C. for 3 h after which sodium cyanoborohydride (28 mg, 0.45 mmol)was added. The reaction was heated at 60° C. for an additional 17 h. Thecrude material was purified by preparative HPLC (10-90ACN/H₂O with 0.1%TFA). The resulting fractions were combined and diluted with EtOAc andwashed with saturated aq NaHCO₃ and water. The organic was dried (MgSO₄)and evaporated to give a 31 mg (0.050 mmol, yield 56%) of the titlecompound as a white solid. ¹H-NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.99 (d,J=2.6 Hz, 1H), 8.64 (dd, J=7.2, 2.5 Hz, 1H), 7.92 (s, 1H), 7.61 (m, 2H),7.52 (m, 1H), 7.42 (m, 3H), 3.94 (s, 2H), 3.71 (br s, 2H), 3.56 (m, 4H),3.37 (m, 2H), 3.21 (s, 3H), 2.69 (m, 2H), 2.43 (m, 4H); MS [M+H]⁺=617.1;LCMS RT=2.81.

Example 109N-4-[4-amino-6-[(methylamino)methyl]-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 108 was used toprepare the title compound by substituting methylamine for morpholine.¹H-NMR (DMSO-d₆) δ 9.39 (s, 1H), 9.00 (d, J=2.5 Hz, 1H), 8.64 (dd,J=7.2, 2.2 Hz, 1H), 7.94 (s, 1H), 7.63 (m, 2H), 7.53 (m, 1H), 7.42 (m,1H), 7.39 (m, 2H), 4.00 (s, 2H), 3.82 (s, 2H), 3.56 (m, 4H), 2.47 (m,4H) 2.37 (s, 3H); MS [M+H]⁺=573.0; LCMS RT=2.31.

Example 110N-4-[4-amino-6-[(2-methoxyethyl)(methyl)-amino]methyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 108 was used toprepare the title compound by substituting 2-methoxy-N-methylethanaminefor morpholine. ¹H-NMR (DMSO-d₆) δ 9.34 (s, 1H), 8.98 (d, J=2.5 Hz, 1H),8.64 (dd, J=7.3, 2.6 Hz, 1H), 7.89 (s, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.52(m, 1H), 7.41 (m, 1H), 7.36 (d, J=8.5 Hz, 2H), 3.93 (s, 2H), 3.54 (m,4H), 3.43 (m, 2H), 3.31 (m, 2H), 3.17 (s, 3H), 2.43 (m, 4H), 2.39 (m,2H), 1.99 (s, 1H); MS [M+H]⁺=631.2; LCMS RT=2.79.

Example 111 Preparation ofN-{4-[4-amino-6-methyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Step 1: Preparation ofN-{4-[4-amino-6-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

A suspension of Intermediate J (925 mg, 1.84 mmol) in 50 mLtetrahydrofuran was cooled to 0° C. and treated dropwise with 1.0 MDIBAL in THF (18.4 mL, 18.4 mmol). The reaction was allowed to warm tort over 30 min, then quenched with 1 mL MeOH and diluted with 1 L EtOAc.This solution was stirred vigorously with 1 L of aqueous Rochelle's saltfor 18 hours. The organic phase was separated, dried with sodium sulfateand filtered through a plug of silica. Concentration of the solvent andtrituration with ether:hexanes (2:1) provided the title compound as ayellowish powder (697 mg, 82% Yield). ¹H-NMR (DMSO-d₆) δ 9.87 (s, 1H),9.74 (s, 1H), 8.54 (d, J=5 Hz, 1H), 8.06 (s, 1H), 7.83 (s, 1H), 7.66 (s,1H), 7.62 (d, J=8.7 Hz, 2H), 7.37 (d, J=8.7 Hz, 2H), 7.38 to 7.35 (m,1H), 4.95 (t, J=5 Hz, 1H), 4.36 (d, J=5 Hz, 2H); MS [M+H]⁺=461; LCMSRT=2.87 min.

Step 2: Preparation ofN-[4-(4-amino-6-methylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

A suspension ofN-{4-[4-amino-6-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]-triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea(423 mg, 0.930 mmol) in THF 5 (mL) and 1,2-dichloroethane (5 mL) wastreated with thionyl chloride (148 uL, 2.05 mmol) at rt. After 10 minthe reaction appeared complete by RP-HPLC. After 30 min the reaction wasconcentrated under vacuum. The residue was suspended in1,2-dichloroethane and sonicated briefly, then concentrated again undervacuum (2×). The resulting solid (412 mg, 0.86 mmol) was suspended inTHF (20 mL) and cooled to −45° C. This suspension was treated with 1.0 ML-Selectride in THF (8.6 mL, 8.6 mmol). After 15 min the reaction wascomplete by HPLC. The reaction mixture was removed from the ice bath andquenched with MeOH (1 mL), then treated with 1 M sodium hydroxide (2 mL)and 30% hydrogen peroxide (2 mL). After 15 min stirring, the mixture wasdiluted with EtOAc (200 mL) and water (200 mL). The organic layer waswashed with brine and dried with sodium sulfate. Concentration of theorganic layer and trituration with ether:hexanes gave the title compoundas an white powder (323 mg, 0.73 mmol, 84% yield). ¹H-NMR (CD₃OD-d₆) δ8.61 (d, J=8 Hz, 1H), 7.73 (s, 1H), 7.62 (d, J=9 Hz, 2H), 7.48 to 7.50(m, 1H), 7.35 (d, J=9 Hz, 2H), 7.31 to 7.36 (m, 2H), 2.14 (s, 3H); MS[M+H]⁺=445.1; LCMS RT=2.80.

Step 3: Preparation of Title Compound

A mixture of morpholine (35 mg, 41 mmol) and 100 uL acetic acid weresonicated until homogeneous, then treated with 37% aqueous formaldehyde(30 uL, 33 mg, 41 mmol) and the mixture added to a solution ofN-[4-(4-amino-6-methylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea(150 mg, 34 mmol) in 1 mL acetic acid. This mixture was stirred for 16 hat 60° C. and then concentrated in vacuo. The residue was dissolved inmethanol with 5 drops of trifluoroacetic acid and purified by RP-HPLC toprovide the title compound as a white solid (32.3 mg, 17.1% yield).¹H-NMR (DMSO-d₆) δ 9.34 (d, J=9.6 Hz, 1H), 8.94 (bs, 1H), 8.62 (d, J=7.2Hz, 1H), 7.92 (s, 1H), 7.85 (s, 1H), 7.61 (d, J=8.7 Hz, 2H), 7.47 to7.53 (m, m1H), 7.33 to 7.41 (m, 1H), 7.31 (d, J=8.7 Hz, 2H), 3.80 (s,2H), 3.48 to 3.55 (m, 4H), 2.34 to 2.44 (m, 4H); MS [M+H]⁺=544.1; LCMSRT=2.70.

Example 112N-{4-[4-amino-6-methyl-7-(morpholin-4-ylmethyl)pyrrolo-[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

The procedure used for the preparation of Example 111 was used toprepare the title compound by substituting Intermediate L in place ofIntermediate J. 700 mg (72%) of the desired product was isolated. ¹H-NMR(DMSO-d₆) δ 8.64 (dd, J=2.1, 7.2 Hz, 1H), 8.28 (t, J=8.7 Hz, 1H), 7.86(s, 1H), 7.53-7.47 (m, 1H), 7.41-7.37 (m, 1H), 7.28 (dd, J=1.8, 14.1 Hz,1H), 7.14 (dd, J=1.2, 8.4 Hz, 1H), 3.80 (s, 2H), 3.54-3.50 (m, 4H),2.43-2.39 (m, 4H), 1.97 (s, 3H); MS [M+H]⁺=562.2; LCMS RT=2.68.

Example 113N-{4-[4-amino-6-(fluoromethyl)-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 87, usingN-{4-[4-amino-6-(hydroxymethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f]-[1,2,4]triazin-5-yl]-[2-fluoro-5-(trifluoromethyl)-phenyl]urea(which can be prepared using the procedure used for the preparation ofExample 34 substituting Intermediate M for Intermediate K) in place ofExample 85(N-{4-[4-amino-6-formyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f]-[1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea),45 mg (23%) of the desired product was isolated. ¹H-NMR (DMSO-d₆) δ 8.65(dd, J=2.4, 6.9 Hz, 1H), 8.31 (t, J=8.4 Hz, 1H), 7.95 (s, 1H), 7.53-7.47(m, 1H), 7.41-7.37 (m, 1H), 7.30 (dd, J=1.8, 12.3 Hz, 1H), 7.19 (dd,J=1.5, 8.4 Hz, 1H), 5.35 (d, J=49.8 Hz, 2H), 3.92 (s, 2H), 3.54-3.50 (m,4H), 2.43-2.39 (m, 4H); MS [M+H]⁺=579.7; LCMS RT=2.63.

Example 114N-{4-[4-amino-6-(hydroxymethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 62, using Intermediate AJ inplace of Intermediate Y, 200 mg (82%) of the desired product wasisolated. ¹H-NMR (DMSO-d₆) δ 10.14-10.08 (m, 2H), 8.54 (d, J=5.1 Hz,1H), 8.30 (q, J=9.3 Hz, 1H), 8.01 (s, 1H), 7.98 (s, 1H), 7.44-7.35 (m,2H), 7.28-7.19 (m, 1H), 5.06-5.04 (m, 1H), 4.41-4.38 (m, 2H), 3.92 (s,2H), 3.55-3.52 (m, 4H), 2.45-2.42 (m, 4H); MS [M+H]⁺=560.9; LCMSRT=2.45.

Example 115N-{4-[4-amino-6-(fluoromethyl)-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 87, usingN-{4-[4-amino-6-(hydroxymethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoro-methyl)-pyridin-2-yl]urea(which can be prepared using the procedure used for the preparation ofExample 62 substituting Intermediate AJ for Intermediate Y) in place ofExample 85(N-{4-[4-amino-6-formyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f]-[1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoro-methyl)pyridin-2-yl]urea),45 mg (23%) of the desired product was isolated. ¹H-NMR (DMSO-d₆) δ10.16-10.10 (m, 2H), 8.54 (d, J=5.1 Hz, 1H), 8.31 (t, J=8.4 Hz, 1H),8.01 (s, 1H), 7.95 (s, 1H), 7.39-7.19 (m, 3H), 5.35 (d, J=49.8 Hz, 2H),3.92 (s, 2H), 3.53-3.52 (m, 4H), 2.48-2.43 (m, 4H); MS [M+H]⁺=562.7;LCMS RT=2.50.

Example 116N-{4-[4-amino-6-(difluoromethyl)-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 87, using Intermediate AK Step1(N-[4-(4-amino-6-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[4-(trifluoromethyl)pyridin-2-yl]urea)in place of Example 85(N-{4-[4-amino-6-formyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f]-[1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoro-methyl)pyridin-2-yl]urea),18 mg (17%) of the desired product was isolated. ¹H-NMR (DMSO-d₆) δ10.16-10.12 (m, 2H), 9.93 (s, 1H), 8.55 (d, J=5.4 Hz, 1H), 8.31 (t,J=8.4 Hz, 1H), 8.01 (s, 2H), 7.47-7.37 (m, 2H), 7.27-7.23 (m, 1H), 4.12(s, 2H), 3.52-3.48 (m, 4H), 2.46-2.40 (m, 4H); MS [M+H]⁺=581.0; LCMSRT=2.60.

Example 117N-{4-[4-amino-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Step 1: Preparation of 6-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine

To a degassed solution of 6-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine(Intermediate AAE) (316 mg, 1.48 mmol) andBis(diphenylphosphino)ferrocenepalladium dichloride (30 mg, 0.037 mmol)in 1,4-dioxane (10 mL), was added dimethyl zinc (2.97 mL, 5.93 mmol, 2.0M in toluene). The mixture was allowed to stir at 90° C. for 17 hr andthen cooled to 0° C. The reaction was quenched with MeOH (1.0 mL) andpartitioned between ethyl acetate (200 mL) and potassium phosphatedibasic pH 10 buffer (100 mL). The layers were separated and the organicphase was washed with brine, dried (Na₂SO₄), and concentrated todryness. Trituration with Et₂O afforded 175 mg (79%) of the desiredproduct. ¹H-NMR (DMSO-d₆) δ 7.69 (s, 1H), 7.39 (s, 1H), 6.61 (s, 1H),2.18 (s, 3H); MS [M+H]⁺=148.9; LCMS RT=1.16.

Step 2: Preparation of6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

A solution of formaldehyde (0.61 mL, 8.10 mmol, 37% in H₂O) andhomomorpholine hydrochloride (1.11 g, 8.10 mmol) in AcOH (5 mL) wasadded to a stirring solution of6-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (1.00 g, 6.75 mmol) in AcOH(5 mL) at 60° C. The reaction was allowed to stir until all startingmaterial had been consumed as shown by HPLC (1 hr). The reaction mixturewas worked up by diluting with EtOAc and washing 3× with saturatedsodium carbonate solution. The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure. The crude product was trituratedwith Et₂O to obtain 1.37 g (78%) of a light brown powder. ¹H-NMR(DMSO-d₆) δ 7.76 (s, 1H), 7.47 (br s, 2H), 6.65 (s, 1H), 3.85 (s, 2H),3.62 (t, J=5.7 Hz, 2H), 3.55-3.51 (m, 2H), 2.61-2.55 (m, 4H), 2.21 (s,3H), 1.77-1.74 (m, 2H); MS [M+H]⁺=262.0; LCMS RT=1.02.

Step 3: Preparation of5-bromo-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

To a stirring solution of chloroform (20 mL) and6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(650 mg, 2.49 mmol), at −40° C., was added1,3-dibromo-5,5-dimethylhydantoin (356 mg, 1.24 mmol). The mixture wasallowed to stir for 10 minutes while warming to rt. The mixture waspartitioned between ethyl acetate (200 mL) and saturated aqueous Na₂CO₃solution (150 mL). The layers were separated and the organic phase waswashed with brine, dried (Na₂SO₄), and concentrated to dryness.Trituration with acetonitrile afforded 500 mg (59%) of the desiredproduct. ¹H-NMR (DMSO-d₆) δ 7.82 (s, 1H), 3.91 (s, 2H), 3.62 (t, J=5.4Hz, 2H), 3.55-3.53 (m, 2H), 2.61-2.56 (m, 4H), 2.15 (s, 3H), 1.77-1.72(m, 2H); MS [M+H]⁺=339.9, 341.9; LCMS RT=1.09.

Step 4: Preparation of the Title Compound

To a stirred solution of5-bromo-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(100 mg, 0.29 mmol) and tetrakis(triphenylphosphine)-palladium(0) (101mg, 0.088 mmol), in degassed 1,4 dioxane (4.0 mL), was addedIntermediate AAN(1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea)(248 mg, 0.59 mmol), K₂CO₃ (162 mg, 1.18 mmol), and H₂O (0.4 mL). Themixture was degassed and heated (90° C.) for 17 h and then cooled to rt.The mixture was partitioned between ethyl acetate (25 mL) and saturatedaqueous Na₂CO₃ solution (25 mL). The layers were separated and theorganic phase was washed, dried (Na₂SO₄), and concentrated to dryness.The residue was purified by preparative HPLC using a gradient elutionfrom 10% to 70% acetonitrile to obtain 24 mg (15%) of the desiredproduct. ¹H-NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.98-8.97 (m, 1H), 8.63 (dd,J=2.4, 7.2 Hz, 1H), 7.85 (s, 1H), 7.60-7.47 (m, 3H), 7.41-7.33 (m, 1H),7.33 (d, J=8.7 Hz, 2H), 3.95 (s, 2H), 3.66 (t, J=6.0 Hz, 2H), 3.59-3.56(m, 2H), 3.31 (m, 2H), 2.68-2.62 (m, 4H), 2.10 (s, 3H), 1.83-1.75 (m,2H); MS [M+H]⁺=558.1; LCMS RT=2.94.

Example 118N-{4-[4-amino-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 117 Step 4, using IntermediateF(1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea)in place of Intermediate AAN(1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea)49 mg (26%) of the desired product was isolated. ¹H-NMR (DMSO-d₆) δ 9.43(br s, 1H), 9.28 (br s, 1H), 8.66 (dd, J=2.4, 7.2 Hz, 1H), 8.29 (t,J=8.7 Hz, 1H), 7.86 (s, 1H), 7.55-7.48 (m, 1H), 7.43-7.40 (m, 1H), 7.29(dd, J=2.1, 12.3 Hz, 1H), 7.15 (dd, J=1.5, 8.4 Hz, 1H), 4.00 (s, 2H),3.65 (t, J=6.0 Hz, 2H), 3.58-3.56 (m, 2H), 2.68-2.62 (m, 4H), 2.12 (s,3H), 1.81-1.77 (m, 2H); MS [M+H]⁺=576.0; LCMS RT=2.66.

Example 119N-{4-[4-amino-6-methyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

Step 1: Preparation of5-bromo-6-methyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

To a solution of 6-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (350 mg,2.36 mmol) in DMF (5 mL), was added 4-methylenemorpholin-4-ium chloride(Eur. J. Med. Chem. 1989, 24, 379-384) (750 mg, 2.84 mmol) at rt. Thereaction was stirred for 17 hr, cooled to −78° C., and treated with1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (337 mg, 1.18 mmol). Thereaction was allowed to stir for 30 minutes while warming to rt. Themixture was partitioned between ethyl acetate (200 mL) and saturatedaqueous Na₂CO₃ solution (150 mL). The layers were separated and theorganic phase was washed with brine, dried (Na₂SO₄), and concentrated todryness. Trituration with acetonitrile afforded 300 mg (39%) of thedesired product. ¹H-NMR (DMSO-d₆) δ 7.83 (s, 1H), 3.76 (s, 2H),3.50-3.47 (m, 4H), 2.36-2.32 (m, 4H), 2.15 (s, 3H); MS [M+H]⁺=325.9,327.9; LCMS RT=1.10.

Step 2: Preparation of the Title Compound

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 117 Step 4, using5-bromo-6-methyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminein place of5-bromo-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amineand Intermediate AAI(1-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[4-(trifluoromethyl)-pyridin-2-yl]urea)in place of Intermediate AAN(1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea)59 mg (36%) of the desired product was isolated. ¹H-NMR (DMSO-d₆) δ10.19 (s, 1H), 9.52 (br s, 1H), 8.55 (d, J=5.1 Hz, 1H), 8.10 (d, J=8.4Hz, 1H), 7.87 (s, 1H), 7.85 (s, 1H), 7.35 (d, J=4.8 Hz, 1H), 7.23 (s,1H), 7.18 (dd, J=2.1, 8.7 Hz, 1H), 3.80 (s, 2H), 3.53-3.50 (m, 4H),2.42-2.40 (m, 4H), 2.35 (s, 3H), 2.09 (s, 3H); MS [M+H]⁺=541.1; LCMSRT=2.49.

Example 120N-{4-[4-amino-6-methyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 117 Step 4, using the productof step 1, Example 119(5-bromo-6-methyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine)in place of5-bromo-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amineand Intermediate AAH(1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea)in place of Intermediate AAN(1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-urea)28 mg (16%) of the desired product was isolated. ¹H-NMR (DMSO-d₆) δ9.41-9.40 (m, 1H), 8.67 (dd, J=2.1, 7.2 Hz, 1H), 8.58 (s, 1H), 8.01 (d,J=8.1 Hz, 1H), 7.85 (s, 1H), 7.53-7.46 (m, 1H), 7.39-7.35 (m, 1H), 7.22(s, 1H), 7.18-7.15 (m, 1H), 3.80 (s, 2H), 3.53-3.50 (m, 4H), 2.41-2.39(m, 4H), 2.31 (s, 3H), 2.09 (s, 3H); MS [M+H]⁺=558.1; LCMS RT=2.59.

Example 121N-{4-[4-amino-6-methyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N-[2-chloro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 117 Step 4, using the productof step 1, Example 119(5-bromo-6-methyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine)in place of5-bromo-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amineand Intermediate AAL(1-[2-chloro-5-(trifluoromethyl)-phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-urea)in place of Intermediate AAN(1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-urea)44 mg (26%) of the desired product was isolated. ¹H-NMR (DMSO-d₆) δ 9.72(s, 1H), 8.67-8.63 (m, 2H), 7.85 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.60(d, J=8.7 Hz, 2H), 7.39-7.30 (m, 3H), 3.80 (s, 2H), 3.53-3.50 (m, 4H),2.42-2.39 (m, 4H), 2.09 (s, 3H); MS [M+H]⁺=560.2; LCMS RT=2.66.

Example 122N-{4-[4-amino-6-methyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 117 Step 4, using the productof step 1, Example 119(5-bromo-6-methyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine)in place of5-bromo-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amineand Intermediate AAG(1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[4-(trifluoromethyl)pyridin-2-yl]urea)in place of Intermediate AAN(1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea),53 mg (44%) of the desired product was isolated. ¹H-NMR (DMSO-d₆) δ 9.88(s, 1H), 9.75 (s, 1H), 8.54 (d, J=5.1 Hz, 1H), 8.06 (s, 1H), 7.85 (s,1H), 7.63 (d, J=8.4 Hz, 3H), 7.36-7.31 (m, 3H), 3.80 (s, 2H), 3.55-3.50(m, 4H), 2.42-2.39 (m, 4H), 2.09 (s, 3H); MS [M+H]⁺=527.1; LCMS RT=2.34.

Example 123N-{4-[4-amino-6-methyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 117 Step 4, using the productof step 1, Example 119(5-bromo-6-methyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine)in place of5-bromo-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amineand Intermediate AAB(1-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[2-fluoro-5-(trifluoromethyl)-phenyl]urea)in place of Intermediate AAN(1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea)25 mg (14%) of the desired product was isolated. ¹H-NMR (DMSO-d₆) δ9.51-9.45 (m, 2H), 8.63-8.61 (m, 1H), 8.20-8.13 (m, 1H), 7.87 (s, 1H),7.55-7.48 (m, 1H), 7.45-7.39 (m, 1H), 7.33-7.27 (m, 1H), 3.80 (s, 2H),3.53-3.50 (m, 4H), 2.41-2.39 (m, 4H), 2.03 (s, 3H); MS [M+H]⁺=580.1;LCMS RT=2.65.

Example 124N-{4-[4-amino-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

In a manner similar to the procedure described for the preparation ofExample 117 Step 4, using Intermediate AAI(1-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[4-(trifluoromethyl)pyridin-2-yl]urea)in place of Intermediate AAN(1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-urea),24 mg (15%) of the desired product was isolated. ¹H-NMR (DMSO-d₆) δ10.21 (s, 1H), 9.97 (br s, 1H), 8.55 (d, J=5.4 Hz, 1H), 8.12-8.08 (m,1H), 7.88 (s, 1H), 7.84 (s, 1H), 7.36-7.17 (m, 3H), 3.65 (s, 2H), 3.65(t, J=6.0 Hz, 2H), 3.58-3.55 (m, 2H), 2.67-2.62 (m, 4H), 2.35 (s, 3H),2.10 (s, 3H), 1.80-1.76 (m, 2H); MS [M+H]⁺=555.0; LCMS RT=2.48.

Example 1251-{4-[4-amino-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-3-[4-(trifluoromethyl)pyridin-2-yl]urea

In a manner similar to the procedure described for the preparation ofExample 117 Step 4, using Intermediate AAG(1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[4-(trifluoromethyl)pyridin-2-yl]urea)in place of Intermediate AAN(1-[2-fluoro-5-(trifluoromethyl)-phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea),28 mg (15%) of the desired product was isolated. ¹H-NMR (DMSO-d₆) δ 9.89(s, 1H), 9.75 (s, 1H), 8.54 (d, J=5.4 Hz, 1H), 8.06 (s, 1H), 7.85 (s,1H), 7.63 (d, J=8.4 Hz, 2H), 7.37-7.31 (m, 3H), 3.95 (s, 2H), 3.65 (t,J=6.0 Hz, 2H), 3.59-3.55 (m, 2H), 2.67-2.62 (m, 4H), 2.10 (s, 3H),1.80-1.76 (m, 2H); MS [M+H]⁺=540.6; LCMS RT=2.35.

Example 1261-{4-[4-amino-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-3-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

In a manner similar to the procedure described for the preparation ofExample 117 Step 4, using Intermediate AAH(1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea)in place of Intermediate AAN(1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]urea),31 mg (15%) of the desired product was isolated. ¹H-NMR (DMSO-d₆) δ9.42-9.41 (m, 1H), 8.67-8.66 (m, 1H), 8.58 (s, 1H), 8.01 (d, J=8.1 Hz,1H), 7.84 (1H), 7.54-7.46 (m, 1H), 7.31-7.26 (m, 1H), 7.22-7.15 (2H),3.95 (s, 2H), 3.65 (t, J=6.0 Hz, 2H), 3.58-3.54 (m, 2H), 2.67-2.63 (m,4H), 2.31 (s, 3H), 2.10 (s, 3H), 1.80-1.76 (m, 2H); MS [M+H]⁺=571.7;LCMS RT=2.50.

Example 1271-{4-[4-amino-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[4-(trifluoromethyl)pyridin-2-yl]urea

In a manner similar to the procedure described for the preparation ofExample 117 Step 4, using Intermediate AAF(1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[4-(trifluoromethyl)pyridin-2-yl]urea)in place of Intermediate AAN(1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-urea),25 mg (10%) of the desired product was isolated. ¹H-NMR (DMSO-d₆) δ10.23-10.12 (m, 1H), 8.63 (d, J=5.4 Hz, 1H), 8.38 (t, J=8.4 Hz, 1H),8.10 (s, 1H), 7.95 (s, 1H), 7.47-7.46 (m, 1H), 7.39 (dd, J=1.8, 12 Hz,1H), 7.26-7.23 (m, 1H), 4.03 (s, 2H), 3.74 (t, J=6.0 Hz, 2H), 3.67-3.64(m, 2H), 2.79-2.72 (m, 4H), 2.20 (s, 3H), 1.89-1.85 (m, 2H); MS[M+H]⁺=558.9; LCMS RT=2.52.

Example 1281-{4-[4-amino-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[4-(trifluoromethyl)pyridin-2-yl]urea

Step 1: Preparation of1-[4-(4-amino-6-methylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-3-[4-(trifluoromethyl)pyridin-2-yl]urea

A suspension of Intermediate AJ(N-{4-[4-amino-6-(hydroxymethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea)(200 mg, 0.433 mmol) in CH₂Cl₂ (5 mL) was treated with thionyl chloride(129 mg, 1.08 mmol) and allowed to stir for 30 min at rt. The reactionmixture was diluted with dichloroethane (25 mL) and the volatilesremoved under vacuum. The residue was suspended in dichloroethane (25mL) and concentrated a second time. The residue was then placed underhigh vacuum for 1 h. All material was then suspended in THF (10 mL) andcooled to −78° C. L-Selectride (438 mg, 2.29 mmol) was added and thereaction moved to a rt water bath. After 1 h the reaction was quenchedwith MeOH (1 mL) and diluted with 1 N NaOH (4 mL). 2 ml, 30% H₂O₂ (2 mL)was added dropwise, and the reaction allowed to stir for 0.5 h. Themixture was diluted with EtOAc (50 mL) and washed well with sodiumthiosulfate solution and brine. The organic layer was dried with sodiumsulfate and the volatiles removed under vacuum to provide an amorphoussolid. Trituration with CH₂Cl₂ provided the desired compound as a whitesolid (111 mg, 59%). ¹H-NMR (DMSO-d₆) δ 10.10-10.30 (m, 2H), 8.54 (d, 1H, J=5 Hz), 8.28 (t, 1H, J=8 Hz), 8.02 (s, 1H), 7.81 (s, 1 H), 7.60 (s,1 H), 7.36-7.40 (m, 1H), 7.28-7.32 (m, 1H), 7.14-7.18 (m, 1H), 2.10 (s,3H); MS [M+H]⁺=446.0; LCMS RT=2.97 min.

Step 2: Preparation of Title Compound

Morpholine (196 mg, 2.25 mmol) was added to Acetic acid (1 mL) and themixture vigorously shaken for 5 min. The resulting mixture was treatedwith 37% aq formaldehyde (67 mg, 2.24 mmol) and stirred untilhomogeneous. The resulting solution was treated with a solution of1-[4-(4-amino-6-methylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-3-[4-(trifluoromethyl)pyridin-2-yl]ureain 2 mL AcOH and the mixture heated at 80° C. for 14 h. The reaction wasdiluted with EtOAc (50 mL) and washed with sodium carbonate solution.The organic layer was dried with sodium sulfate and concentrated undervacuum. The resulting solid was taken up in 1 mL MeOH with the aid ofTFA (50 uL). Purification by preparative RP-HPLC provided the desiredproduct (41.1 mg, 34%) as a white solid. ¹H-NMR (DMSO-d₆) δ 10.25 (s,1H), 10.19 (bs, 1H), 9.98 (bs, 1H), 8.63 (d, 1H, J=5 Hz), 8.36-8.44 (m,1H), 8.11 (s, 1H), 8.09 (s, 1 H), 7.43-7.50 (m, 1H), 7.38 (dd, 1H, J=12,2 Hz), 7.24 (dd, 1H, J=8, 1 Hz), 4.78 (s, 2H), 3.97-4.08 (m, 2H),3.68-3.81 (m, 1H), 3.40-3.55 (m, 2H), 3.23-3.45 (m, 2H), 2.27 (s, 3H);MS [M+H]⁺=545.1; LCMS RT=2.56 min.

Example 129N-(4-{4-amino-6-(cyanomethyl)-7-[(2,6-dimethylmorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 62 was used to preparethe title compound by substituting Intermediate AS for Intermediate Yand by substituting 2,6-dimethylmorpholine for morpholine. ¹H-NMR(CD₃OD-d₄) δ 9.53 (s, 1H), 8.93 (s, 1H), 8.66 (s, 1H), 8.42-8.37 (m,1H), 8.05 (s, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.37-7.23 (m, 3H), 4.85 (s,2H), 3.91 (s, 2H), 3.94-3.88 (m, 2H), 3.52 (t, J=8.0 Hz, 2H), 2.93 (t,J=8.0 Hz, 2H), 1.24 (d, J=6.4 Hz, 6H); MS [M+H]⁺=631.1; LCMS RT=3.07.

Example 1301-{4-[4-amino-6-(methoxymethyl)-7-(1,4-oxazepan-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used to prepare Example 26 was used to prepare the titlecompound by substituting Intermediate AB(N-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea)for Intermediate Q and homomorpholine for morpholine. ¹H-NMR (DMSO-d₆) δ9.44 (d, J=2.6, 1H), 9.29 (d, J=2.3, 1H), 8.65 (dd, J=7.3, 2.3, 1H),8.28 (t, J=8.7, 1H), 7.91 (s, 1H), 7.54 to 7.48 (m, 1H), 7.43 to 7.38(m, 1H), 7.33 (dd, J=12.3, 1.8, 1H), 7.19 (dd, J=8.4, 1.7), 1H), 4.33(s, 2H), 4.00 (s, 2H), 3.65 (t, J=6.2), 2H), 3.59 to 3.54 (m, 2H), 3.19(s, 3H), 2.71 to 2.63 (m, 4H), 1.82 to 1.74 (m, 2H); MS [M+H]⁺=605.7;LCMS RT=2.61.

Example 131N-{4-[4-amino-6-(methoxymethyl)-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(2-fluoro-5-methyl-phenyl)urea

The procedure used to prepare Example 26 was used to prepare the titlecompound by substituting1-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]-triazin-5-yl]-2-fluorophenyl}-3-(2-fluoro-5-methylphenyl)ureafor Intermediate Q. ¹H-NMR (DMSO-d₆) δ 9.15 (d, J=2.8, 1H), 9.04 (d,J=2.4, 1H), 8.29 (t, J=8.8, 1H), 8.02 (dd, J=8.0, 2.0, 1H), 7.91 (s,1H), 7.31 (dd, J=12.4, 2.0, 1H), 7.17 (dd, J=8.4, 2.0, 1H), 7.11 (dd,J=11.6, 8.4, 1H), 6.83 to 6.79 (m, 1H), 4.31 (s, 2H), 3.86 (s, 2H), 3.52(t, J=4.4, 4H), 3.19 (s, 3H), 2.43 (t, J=4.0, 4H), 2.26 (s, 3H); MS[M+H]⁺=538.0; LCMS RT=2.42.

Example 132N-{4-[4-amino-6-(methoxymethyl)-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(3-methylphenyl)urea

The procedure used to prepare Example 26 was used to prepare the titlecompound by substituting1-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-(3-methylphenyl)ureafor Intermediate Q. ¹H-NMR (DMSO-d₆) δ 9.05 (s, 1H), 8.66 (d, J=2.4,1H), 8.27 (t, J=8.4, 1H), 7.91 (s, 1H), 7.32 to 7.28 (m, 2H), 7.23 (d,J=8.8, 1H), 7.18 to 7.14 (m, 2H), 6.80 (d, J=6.8, 1H), 4.30 (s, 2H),3.86 (s, 2H), 3.51 (t, J=4.4, 4H), 3.19 (s, 3H), 2.43 (t, J=4.0, 4H),2.27 (s, 3H); MS [M+H]⁺=520.0; LCMS RT=2.35.

Example 133N-{4-[4-amino-6-(methoxymethyl)-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[3-(trifluoro-methyl)-phenyl]urea

The procedure used to prepare Example 26 was used to prepare the titlecompound by substituting1-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[3-(trifluoromethyl)phenyl]ureafor Intermediate Q. ¹H-NMR (DMSO-d₆) δ 9.49 (s, 1H), 8.78 (d, J=2.4,1H), 8.23 (t, J=8.4, 1H), 8.05 (s, 1H), 7.92 (s, 1H), 7.56 to 7.50 (m,2H), 7.34 to 7.30 (m, 2H), 7.18 (dd, J=8.4, 1.6, 1H), 4.31 (s, 2H), 3.86(s, 2H), 3.52 (t, J=4.4, 4H), 3.19 (s, 3H), 2.43 (t, J=4.0, 4H); MS[M+H]⁺=574.0; LCMS RT=2.53.

Example 134N-{4-[4-amino-6-(methoxymethyl)-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(4-methylpyridin-2-yl)urea

The procedure used to prepare Example 26 was used to prepare the titlecompound by substituting1-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-(4-methylpyridin-2-yl)ureafor Intermediate Q. ¹H-NMR (DMSO-d₆) δ 9.85 (s, 1H), 8.33 (t, J=8.4,1H), 8.12 (d, J=5.2, 1H), 7.91 (s, 1H), 7.33 (dd, J=12.4, 2.0, 1H), 7.19(dd, J=8.8, 2.0, 1H), 7.17 to 7.14 (m, 1H), 6.88 (dd, J=5.2, 1.6, 1H),4.30 (s, 2H), 3.86 (s, 2H), 3.52 (t, J=4.4, 4H), 3.19 (s, 3H), 2.43 (t,J=4.0, 4H), 2.29 (s, 3H); MS [M+H]⁺=521.0; LCMS RT=1.98.

Example 135N-{4-[4-amino-6-(methoxymethyl)-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(4-tert-butylpyridin-2-yl)urea

The procedure used to prepare Example 26 was used to prepare the titlecompound by substituting1-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-(4-tert-butylpyridin-2-yl)ureafor Intermediate Q. ¹H-NMR (DMSO-d₆) δ 9.82 (s, 1H), 8.33 (t, J=8.8,1H), 8.17 (d, J=5.2, 1H), 7.92 (s, 1H), 7.40 to 7.36 (m, 1H), 7.33 (dd,J=12.0, 2.0, 1H), 7.19 (dd, J=8.8, 1.6, 1H), 7.08 (dd, J=5.6, 1.6, 1H),4.30 (s, 2H), 3.86 (s, 2H), 3.52 (t, J=4.4, 4H), 3.19 (s, 3H), 2.43 (t,J=4.0, 4H), 1.25 (s, 9H); MS [M+H]⁺=563.2; LCMS RT=2.87.

Example 136N-{4-[4-amino-6-(methoxymethyl)-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used to prepare Example 26 was used to prepare the titlecompound by substituting Intermediate AL(1-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[4-(trifluoro-methyl)pyridin-2-yl]urea)for Intermediate Q. ¹H-NMR (DMSO-d₆) δ 10.16 (s, 1H), 10.10 (s, 1H),8.54 (d, J=5.2, 1H), 8.29 (t, J=8.4, 1H), 8.00 (s, 1H), 7.92 (s, 1H),7.38 (dd, J=5.2, 1.2, 1H), 7.37 (dd, J=12.0, 2.0, 1H), 7.20 (dd, J=8.4,1.2, 1H), 4.31 (s, 2H), 3.86 (s, 2H), 3.52 (t, J=4.4, 4H), 3.19 (s, 3H),2.43 (t, J=4.0, 4H); MS [M+H]⁺=575.3; LCMS RT=3.02.

Example 137N-{4-[4-amino-6-(methoxymethyl)-7-(1,4-oxazepan-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(3-tert-butylphenyl)urea

The procedure used to prepare Example 26 was used to prepare the titlecompound by substituting1-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-(3-tert-butylphenyl)ureafor Intermediate Q and homomorpholine for morpholine. ¹H-NMR (DMSO-d₆) δ9.45 (s, 1H), 8.81 (s, 1H), 8.25 (t, J=9.2, 1H), 7.90 (s, 1H), 7.48 (t,J=2.4, 1H), 7.32 to 7.27 (m, 2H), 7.22 to 7.14 (m, 2H), 7.02 (d, J=8.0,1H), 4.32 (s, 2H), 4.00 (s, 2H), 3.65 (t, J=6.0, 2H), 3.57 (br t, J=4.4,2H), 3.19 (s, 3H), 2.69 to 2.65 (m, 4H), 1.81 to 1.75 (m, 2H), 1.26 (s,9H); MS [M+H]⁺=576.2; LCMS RT=2.92.

Example 138N-{4-[4-amino-6-(methoxymethyl)-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(3-tert-butylphenyl)urea

The procedure used to prepare Example 26 was used to prepare the titlecompound by substituting1-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-(3-tert-butylphenyl)ureafor Intermediate Q. ¹H-NMR (DMSO-d₆) δ 9.11 (s, 1H), 8.62 (d, J=2.4,1H), 8.27 (t, J=8.4, 1H), 7.91 (s, 1H), 7.45 (t, J=2.0, 1H), 7.32 to7.28 (m, 2H), 7.23 to 7.15 (m, 2H), 7.02 (d, J=8.0, 1H), 4.30 (s, 2H),3.86 (s, 2H), 3.52 (t, J=4.4, 4H), 3.19 (s, 3H), 2.43 (t, J=4.0, 4H),1.27 (s, 9H); MS [M+H]⁺=562.2; LCMS RT=3.05.

Example 139N-{4-[4-amino-6-(methoxymethyl)-7-(1,4-oxazepan-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea

The procedure used to prepare Example 26 was used to prepare the titlecompound by substituting1-{-4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[3-(trifluoromethyl)phenyl]ureafor Intermediate Q and homomorpholine for morpholine. ¹H-NMR (DMSO-d₆) δ9.64 (s, 1H), 8.93 (s, 1H), 8.21 (t, J=9.2, 1H), 8.06 (s, 1H), 7.91 (s,1H), 7.58 to 7.50 (m, 2H), 7.30 to 7.35 (m, 2H), 7.18 (dd, J=8.4, 2.0,1H), 4.33 (s, 2H), 4.00 (s, 2H), 3.65 (t, J=6.0, 2H), 3.57 (br t, J=4.4,2H), 3.19 (s, 3H), 2.69 to 2.65 (m, 4H), 1.80 to 1.75 (m, 2H); MS[M+H]⁺=588.0; LCMS RT=2.57.

Example 140N-{4-[4-amino-6-(methoxymethyl)-7-(1,4-oxazepan-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(2-fluoro-5-methylphenyl)urea

The procedure used to prepare Example 26 was used to prepare the titlecompound by substituting1-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]-triazin-5-yl]-2-fluorophenyl}-3-(2-fluoro-5-methylphenyl)-ureafor Intermediate Q and homomorpholine for morpholine. ¹H-NMR (DMSO-d₆) δ9.16 (d, J=2.8, 1H), 9.04 (d, J=2.8, 1H), 8.28 (t, J=8.8, 1H), 8.02 (dd,J=7.2, 1.6, 1H), 7.91 (s, 1H), 7.31 (dd, J=12.0, 2.0, 1H), 7.17 (dd,J=8.4, 1.6, 1H), 7.11 (dd, J=11.2, 8.0, 1H), 6.83 to 6.79 (m, 1H), 4.32(s, 2H), 4.00 (s, 2H), 3.65 (t, J=6.0, 2H), 3.57 (br t, J=4.4, 2H), 3.19(s, 3H), 2.69 to 2.64 (m, 4H), 2.26 (s, 3H), 1.80 to 1.74 (m, 2H); MS[M+H]⁺=552.1; LCMS RT=2.46.

Example 141N-{4-[4-amino-6-(methoxymethyl)-7-(1,4-oxazepan-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea

The procedure used to prepare Example 26 was used to prepare the titlecompound by substituting1-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-chloro-5-(trifluoromethyl)phenyl]ureafor Intermediate Q and homomorpholine for morpholine. ¹H-NMR (DMSO-d₆) δ9.67 (s, 1H), 9.17 (s, 1H), 8.63 (d, J=2.4, 1H), 8.27 (t, J=8.8, 1H),7.91 (s, 1H), 7.73 (d, J=8.4, 1H), 7.39 (dd, J=8.8, 2.4, 1H), 7.33 (dd,J=12.0, 1.6, 1H), 7.19 (dd, J=8.4, 2.0, 1H), 4.33 (s, 2H), 4.00 (s, 2H),3.65 (t, J=6.0, 2H), 3.57 (br t, J=4.4, 2H), 3.19 (s, 3H), 2.69 to 2.65(m, 4H), 1.80 to 1.75 (m, 2H); MS [M+H]⁺=622.1; LCMS RT=2.69.

Example 142N-{4-[4-amino-6-(methoxymethyl)-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea

The procedure used to prepare Example 26 was used to prepare the titlecompound by substituting1-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-chloro-5-(trifluoromethyl)phenyl]ureafor Intermediate Q. ¹H-NMR (DMSO-d₆) δ 9.65 (s, 1H), 9.16 (s, 1H), 8.63(d, J=2.4, 1H), 8.28 (t, J=8.4, 1H), 7.92 (s, 1H), 7.73 (d, J=8.4, 1H),7.39 (dd, J=8.8, 2.4, 1H), 7.33 (dd, J=12.0, 1.6, 1H), 7.19 (dd, J=8.4,2.0, 1H), 4.31 (s, 2H), 3.86 (s, 2H), 3.52 (t, J=4.4, 4H), 3.19 (s, 3H),2.43 (t, J=4.0, 4H); MS [M+H]⁺=609.0; LCMS RT=2.66.

Example 143 Preparation ofN-4-[4-amino-6-(methoxymethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a flask charged with N₂ was added5-bromo-6-(methoxymethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(1 eq) (Intermediate AAA) and1-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[2-fluoro-5-(trifluoromethyl)-phenyl]urea(Intermediate AAB) (1 eq) followed by 1,4-dioxane (0.1 M). Nitrogen wasbubbled through the solution for 15 min and thendichlorobis(triphenylphosphine)palladium(II) (229 mg, 0.1 eq) was addedfollowed by aq 1 M Na₂CO₃ (2 eq). N₂ was bubbled through the solutionfor an additional 15 min and, then the reaction was heated to 80° C. for17 h. The reaction material was allowed to cool to rt and was dilutedwith EtOAc and water. The solution was separated and the aqueous layerwas back extracted with EtOAc. The organic fractions were combined,dried (MgSO₄), filtered, condensed, and purified by flash columnchromatography (9:1 CH₂Cl₂/MeOH). The material was further purified byflash column chromatography (50:47:3 CH₂Cl₂/EtOAc/MeOH). The purifiedfractions were collected, evaporated, and left under vacuum overnight toyield the title compound. ¹H-NMR (DMSO-d₆) δ 9.51 (s, 1H), 9.47 (s, 1H),8.64 (d, J=7.2 Hz, 1H), 8.18-8.13 (m, 1H), 7.92 (s, 1H), 7.55-7.50 (m,1H), 7.45-7.41 (m, 1H), 7.36-7.31 (m, 1H), 4.43 (d, J=11.5 Hz, 1H), 4.22(d, J=11.5 Hz, 1H), 3.86 (s, 2H), 3.54-3.51 (m, 4H), 3.09 (s, 3H),2.43-2.39 (m, 4H); MS [M+H]⁺=610; LCMS RT=2.81.

Example 144 Preparation ofN-4-[4-amino-6-(methoxymethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 143 was used toprepare the title compound by substituting Intermediate AAH(1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea)for Intermediate AAB(1-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[2-fluoro-5-(trifluoromethyl)-phenyl]urea).¹H-NMR (DMSO-d₆) δ 9.42 (s, 1H), 8.67 (d, J=7.4 Hz, 1H), 8.58 (s, 1H),8.02 (d, J=8.3 Hz, 1H), 7.90 (s, 1H), 7.53-7.48 (m, 1H), 7.40-7.36 (m,1H), 7.27 (s, 1H), 7.22 (d, J=7.6 Hz, 1H), 4.30 (s, 2H), 3.86 (s, 2H),3.53-3.51 (m, 4H), 3.18 (s, 3H), 2.44-2.41 (m, 4H), 2.31 (s, 3H); MS[M+H]⁺=588; LCMS RT=2.61.

Example 145 Preparation ofN-4-[4-amino-6-(methoxymethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Example 143 was used toprepare the title compound by substituting Intermediate AAI1-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[4-(trifluoromethyl)pyridin-2-yl]ureafor Intermediate AAB(1-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea).¹H-NMR (DMSO-d₆) δ 10.19 (s, 1H), 10.00-9.94 (br s), 8.55 (d, J=5.4 Hz,1H), 8.11 (d, J=8.5 Hz, 1H), 7.90 (s, 1H), 7.87 (s, 1H), 7.36 (d, J=5.3Hz, 1H), 7.30 (s, 1H), 7.24 (d, J=8.3 Hz, 1H), 4.30 (s, 2H), 3.86 (s,2H), 3.53-3.51 (m, 4H), 3.17 (s, 3H), 2.44-2.42 (m, 4H), 2.35 (s, 3H);MS [M+H]⁺=571; LCMS RT=2.50.

Example 146 Preparation of1-4-[4-amino-7-[(2-hydroxyethyl)amino]methyl-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 12 was used to preparethe title compound by substituting Intermediate AAC(1-{4-[4-amino-7-formyl-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea)for Intermediate AW(N-{4-[4-amino-7-formyl-6-(methoxymethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea)and 2-aminoethanol for morpholine. ¹H-NMR (DMSO-d₆) δ 9.47 (s, 1H), 9.32(s, 1H), 8.66 (d, J=7.3 Hz, 1H), 8.30 (t, J=8.5 Hz, 1H), 7.95 (s, 1H),7.54-7.49 (m, 1H), 7.43-7.39 (m, 1H), 7.30 (d, J=12.1 Hz, 1H), 7.17 (d,J=8.9 Hz, 1H), 4.68-4.64 (br s, 1H), 4.31 (s, 2H), 4.28 (s, 2H),3.50-3.46 (m, 2H), 3.20 (s, 3H), 2.70-2.66 (m, 2H); MS [M+H]⁺=566; LCMSRT=2.54.

Example 147 Preparation of1-{4-[4-amino-6-(methoxymethyl)-7-{[(3S)-3-methylmorpholin-4-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 12 was used to preparethe title compound by substituting Intermediate AAC(1-{4-[4-amino-7-formyl-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea)for Intermediate AW(N-{4-[4-amino-7-formyl-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoro-methyl)phenyl]urea)and 3-(S)-methylmorpholine for morpholine. ¹H-NMR (DMSO-d₆) δ 9.45 (s,1H), 9.29 (s, 1H), 8.66 (d, J=6.9 Hz, 1H), 8.29 (t, J=8.5 Hz, 1H), 7.92(s, 1H), 7.54-7.50 (m, 1H), 7.43-7.39 (m, 1H), 7.33 (d, J=12.1 Hz, 1H),7.19 (d, J=8.1 Hz, 1H), 4.40 (d, J=11.1 Hz, 1H), 4.26 (d, J=12.1 Hz,2H), 3.67-3.57 (m, 3H), 3.20 (s, 3H), 3.10 (t, J=10.5 Hz, 1H), 2.45-2.41(m, 1H), 2.21 (t, J=10.1 Hz, 1H), 1.09 (d, J=6.2 Hz, 3H); MS [M+H]⁺=606;LCMS RT=2.70.

Example 148N-{4-[4-amino-6-ethyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

Step 1. Preparation of1-[4-(4-amino-6-vinylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-3-[4-(trifluoromethyl)pyridin-2-yl]urea

Potassium tert-butoxide (1.0 g, 9.06 mmol) was suspended in 1,4-dioxane(20 mL) and treated with methyltriphenylphosphonium bromide (3.2 g, 9.06mmol). The mixture was allowed to stir at rt for 30 min. A yellowsuspension formed then Intermediate AF(1-[4-(4-amino-6-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-3-[4-(trifluoromethyl)-pyridin-2-yl]urea)(2.0 g, 4.53 mmol) in 1,4-dioxane (10 mL) was slowly added and thereaction was stirred at rt for 4 hr. The reaction was slowly poured intovigorously stirring water. The mixture was allowed to stir for 1 hr. Thesolid was filtered and rinsed with water and MeOH. A light brown solidwas isolated (1.2 g, 60%). ¹H-NMR (DMSO-d₆) δ 9.90 (s, 1H), 9.77 (s,1H), 8.53 (d, J=5.2 Hz, 1H), 8.06-8.05 (m, 2H), 7.84 (s, 1H), 7.64 (d,J=8.5 Hz, 2H), 7.36 (d, J=5.4 Hz, 1H), 7.31 (d, J=8.5 Hz, 2H), 6.39 (dd,J₁=11.3, J₂=17.6 Hz, 1H), 5.63 (dd, J₁=1.7, J₂=17.5 Hz, 1H), 5.12 (dd,J₁=1.5, J₂=11.1 Hz, 2H). MS [M+H]⁺=440.0; LCMS RT=2.88.

Step 2. Preparation of1-[4-(4-amino-6-ethylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-3-[4-(trifluoromethyl)pyridin-2-yl]urea

1-[4-(4-amino-6-vinylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-3-[4-(trifluoro-methyl)pyridin-2-yl]urea(150 mg, 0.341 mmol) was slowly dissolved in THF (100 mL) by addingacetic acid (10-20 mL). The solution was further diluted with EtOH (300mL) and run through the H-Cube® apparatus at 20 bar, rt, 1 mL/min. Theresulting solution was concentrated then washed with satd. NaHCO₃. Aprecititate formed and the desired product was collected by vacuumfiltration to yield a tan solid. (150 mg, 99%). ¹H-NMR (DMSO-d₆) δ 11.89(bs, 2H), 8.49 (d, J=5.0 Hz, 1H), 8.28 (s, 1H), 7.80 (s, 1H), 7.74 (d,J=8.8 Hz, 2H), 7.60 (s, 1H), 7.27 (m, 3H), 2.48 (q, J=7.8 Hz, 2H), 1.09(t, J=7.5 Hz, 3H). MS [M+H]⁺=442.0; LCMS RT=2.95.

Step 3. Preparation of Title Compound

A solution of1-[4-(4-amino-6-ethylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-3-[4-(trifluoromethyl)pyridin-2-yl]urea(120 mg, 0.7 mmol) in acetic acid (2 mL) was treated with a mixture ofmorpholine (240 μL, 2.72 mmol) and formaldehyde (37%, 204 μL, 2.72 mmol)in acetic acid (1 mL). The reaction was heated to 60° C. overnight. Thereaction was then diluted with EtOAc and washed with NaHCO₃. The organiclayer was dried (MgSO₄) and concentrated. The pale orange solid was thentriturated with ether. The desired product was collected by vacuumfiltration (30 mg, 20%). ¹H-NMR (DMSO-d₆) δ 9.95 (bs, 1H), 9.82 (bs,1H), 8.55 (d, J=4.1 Hz, 1H), 8.07 (s, 1H), 7.86 (s, 1H), 7.64 (d, J=6.8Hz, 2H), 7.38-7.32 (m, 3H), 3.82 (s, 2H), 3.53-3.50 (m, 4H), 2.54-2.49(m, 2H), 2.44-2.41 (m, 4H), 0.97 (t, J=7.5 Hz, 3H). MS [M+H]⁺=541.1;LCMS RT=2.86.

Example 1491-{4-[4-amino-6-(methoxymethyl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Step 1: Preparation of tert-butyl4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate

A 2 M solution of lithium diisopropylamide inheptane/tetrahydrofuran/ethylbenzene (20 mL; 0.04 Mol) was stirred undernitrogen atmosphere while cooling −78° C., and a solution of1-BOC-4-piperidone (6.79 g; 0.033 Mol) in tetrahydrofuran (50 mL) added(internal temperature <−50° C.). After 10 min. a solution ofN-phenyltrifluoromethanesulfonimide in tetrahydrofuran (50 mL) was added(internal temperature <−60° C.). After 1 hr. the cooling bath wasremoved, and the mixture allowed to warm to rt. After 3 h, the mixturewas poured into stirred brine (300 mL) and extracted with hexanes (3×100mL). The combined organic extracts had a lower, orange liquid phase,which was separated and discarded. The resulting organic phase waswashed with brine, dried (anhydrous sodium sulfate), filtered andconcentrated to afforded 16.45 g of orange brown oil, which was purifiedby silica gel chromatography (hexanes/dichloromethane gradient). Theredesired product (8.15 g, 74% yield) was obtained as an orange-yellowoil. ¹H-NMR (CD₂Cl₂) δ 5.78 (d, 1 H), 4.03 (q, 2 H), 3.61 (t, 2 H), 2.43(d, 2 H), 1.45 (s, 9 H).

Step 2: Preparation oftert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate

A stirred mixture of tert-butyl4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate(61.4 g, 0.185 Mol), bis(pinacolato)diboron (51.77 g, 0.204 Mol) andpotassium acetate (54.56 g, 0.556 Mol) in dioxane (2.0 L) was degassedwith nitrogen for 20 minutes.Dichloro[bis(diphenylphosphino)ferrocene]palladium (II) dichloromethaneadduct (4.07 g, 6.0 mMol) was then added, and the mixture was stirred at80° C. under nitrogen atmosphere. After 1 hr, the mixture was cooled tort, and filtered through Celite. The filtrate was concentrated in vacuo,and the residue purified by silica gel chromatography(hexanes/dichloromethane/ethyl acetate gradient) to afford 29.07 g (51%yield) of the desired product as a colorless, fluffy solid (38-3).¹H-NMR (CD₂Cl₂) δ 6.41 (d, 1H), 3.91 (q, 2H), 3.40 (t, 2H), 2.16 (m,2H), 1.43 (s, 9H), 1.23 (s, 12H).

Step 3: Preparation of tert-butyl4-{4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl}-3,6-dihydropyridine-1(2H)-carboxylate

To a flask charged with N₂ was added1-{4-[4-amino-7-bromo-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea(Intermediate AAC, Step 1) (500 mg, 0.875 mmol, 1.0 eq) andtert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(677 mg, 2.19 mmol, 2.5 eq) followed by 1,4-dioxane (5 mL). Nitrogen wasbubbled through the solution for 15 min and then 2M Na₂CO₃ (6 eq) wasadded. Nitrogen again bubbled through solution for 15 minutes and[1,1′-Bis(dipheylphosphino)ferrocene] (143 mg, 0.2 eq) was added. N₂ wasbubbled through the solution for an additional 15 min and then thereaction was placed in a preheated 80° C. oil bath for 17 h. Thereaction solution was allowed to cool to rt and was diluted with EtOAcand water. The organic layer was washed water and brine. The combinedorganic layers were dried (Na₂SO₄), filtered, condensed, and purifiedvia flash column chromatography (1:1 tetrahydrofuran/hexanes). Thepurified fractions were collected, evaporated, and left under vacuumovernight to yield the title compound (520 mg, 88.2% yield). ¹H-NMR(DMSO-d₆) MS [M+H]⁺=674; LCMS RT=3.51 min.

Step 4: Preparation of tert-butyl4-{4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl}piperidine-1-carboxylate

To a flask charged with N₂ was added tert-butyl4-{4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]-6-(methoxymethyl)-pyrrolo-[2,1-f][1,2,4]triazin-7-yl}-3,6-dihydropyridine-1(2H)-carboxylate(424 mg, 0.629 mmol, 1.0 eq) followed by glacial acetic acid (40 mL). Tothis solution was added platinum oxide (42 mg, 10% w/w). The reactionsolution was evacuated via vacuum and replaced with nitrogen (5×). Thereaction mixture was then evacuated again via vacuum and placed under 1atm of hydrogen and was allowed to stir for 17 hours. The solution wasfiltered through a pad of celite, washed with acetic acid andconcentrated. The crude concentrate was dissolved in EtOAc and washedwith saturated sodium bicarbonate. The organic layer was dried (Na₂SO₄),filtered, condensed, and purified via flash chromatography (1:1tetrahydrofuran/hexanes). The purified fractions were collected,evaporated, and left under vacuum overnight to yield the title compound(320 mg, 75.3% yield). ¹H-NMR (DMSO-d₆) MS [M+H]⁺=676; LCMS RT=3.52 min.

Step 5: Preparation of Title Compound

To a flask charged with tert-butyl4-{4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl}piperidine-1-carboxylatewas added methylene chloride (12.5 mL). To this suspension was added12.5 mL of trifluoroacetic acid. The homogeneous solution was allowed tostir at rt under nitrogen for 17 hours. The reaction mixture wasconcentrated and the residue dissolved in EtOAc. The organic phase waswashed with saturated sodium bicarbonate solution (2×), brine (1×),separated and the organic layer dried (Na₂SO₄). The organic layer wasfiltered, concentrated and left under vacuum overnight to yield thetitle compound (150 mg, 70.4% yield). ¹H-NMR (DMSO-d₆) MS [M+H]⁺=576;LCMS RT=2.51 min.

Example 1504-{4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)-phenyl]carbamoyl}amino)phenyl]-6-(methoxymethyl)-pyrrolo[2,1f][1,2,4]-triazin-7-yl}-N,N-dimethylpiperidine-1-carboxamide

To a flask charged with N₂ was added1-{4-[4-amino-6-(methoxymethyl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoro-methyl)phenyl]urea(Example 149) (30 mg, 0.052 mmol, 1.0 eq) and 1,2-dichloroethane (2 mL).Tetrahydrofuran was added dropwise until the reaction mixture was acomplete solution. The solution was cooled to 0° C. anddimethylcarbomoyl chloride (4.7 μl, 1 eq) was added. The reactionmixture was allowed to gradually warm to rt over 17 hours. The reactionwas concentrated and the residue dissolved in EtOAc. The organic phasewas washed with saturated sodium bicarbonate solution (2×), brine (1×),separated and the organic layer dried (Na₂SO₄). The organic layer wasfiltered, concentrated and purified via flash column chromatography (6:4tetrahydrofuran/hexanes). The purified fractions were collected,concentrated, stirred in hexanes and filtered. The filtrate was placedunder vacuum overnight to yield the title compound (6 mg, 17.8% yield).¹H-NMR (DMSO-d₆) δ 9.44 (s, 1H), 9.29 (s, 1H), 8.65 (d, J=6.5 Hz, 1H),8.29 (t, J=8.5 Hz, 1H), 7.89 (s, 1H), 7.51 (t, J=9.9 Hz, 1H), 7.41 (m,1H), 7.29 (dd, J=12.3, 1.7 Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 4.23 (s,2H), 3.68 (m, 2H), 3.44 (m, 1H), 3.16 (s, 3H), 2.75 (s, 6H), 2.26 (m,2H), 1.64 (m, 2H); MS [M+H]⁺=647; LCMS RT=3.03 min.

Example 1514-{4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)-phenyl]carbamoyl}amino)phenyl]-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]-triazin-7-yl}-N-methylpiperidine-1-carboxamide

To a flask charged with N₂ was added1-{4-[4-amino-6-(methoxymethyl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoro-methyl)phenyl]urea(Example 149) (30 mg, 0.052 mmol, 1.0 eq) and 1,2-dichloroethane (2 mL).Tetrahydrofuran was added dropwise until the reaction mixture was acomplete solution. The solution was cooled to 0° C. and methylisocyanate (5.2 μl, 1 eq) is added. The reaction mixture was allowed togradually warm to rt over 17 hours. The reaction was concentrated andthe residue dissolved in EtOAc. The organic phase was washed withsaturated sodium bicarbonate solution (2×), brine (1×), separated andthe organic layer dried (Na₂SO₄). The organic layer was filtered,concentrated and purified via flash column chromatography(tetrahydrofuran). The purified fractions were collected, concentrated,stirred in hexanes and filtered. The filtrate was placed under vacuumovernight to yield the title compound (18 mg, 32.8% yield). ¹H-NMR(DMSO-d₆) δ 9.44 (s, 1H), 9.29 (s, 1H), 8.65 (d, J=7.2 Hz, 1H), 8.29 (t,J=8.4 Hz, 1H), 7.88 (s, 1H), 7.51 (t, J=9.9 Hz, 1H), 7.41 (m, 1H), 7.2(dd, J=12.1, 1.9 Hz, 1H), 7.1 (dd, J=8.5, 1.4 Hz, 1H), 4.22 (s, 2H),4.06 (m, 2H), 3.42 (m, 1H), 3.15 (s, 3H), 2.73 (t, J=12.4 Hz, 2H), 2.57(d, J=4.3 Hz, 3H) 2.17 (m, 2H), 1.59 (m, 2H); MS [M+H]⁺=633; LCMSRT=2.97 min.

Example 152N-{4-[4-amino-6-chloro-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

To a solution of Intermediate AAD(5-bromo-6-chloro-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine)(0.04 g, 0.12 mmol) in DMF (2 mL) was added Intermediate F(N-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea)(0.06 g, 0.14 mmol) and tetrakis(triphenylphosphine) palladium (0.013 g,0.012 mmol) under nitrogen atmosphere. The reaction mixture was degassed3× and then microwaved for 10 minutes at 120° C. Upon cooling to rt, themixture was filtered through a celite pad and DMF was removed underreduced pressure. The crude material was then purified by HPLC (0-70acetonitrile/water) to yield 40 mg of the above compound (0.07 mmol,yield 60%). ¹H-NMR (CD₃OD-d₄) δ 8.65 (d, J=7.6 Hz, 1H), 8.40-8.35 (m,1H), 8.06 (s, 1H), 7.37-7.25 (m, 4H), 4.82 (s, 2H), 4.15-3.72 (m, 4H),3.60-3.41 (m, 4H); MS [M+H]⁺=581.9; LCMS RT=2.66 min.

Example 153N-{4-[4-amino-6-chloro-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared using the procedure to make Example 152by substituting Intermediate AAL(1-[2-chloro-5-(trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea)for Intermediate F. ¹H-NMR (CD₃OD-d₄) δ 8.66 (d, J=2.4 Hz, 1H), 8.05 (s,1H), 7.68 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.0 Hz, 1H), 7.45 (d, J=8.8 Hz,2H), 7.36-7.32 (m, 1H), 4.83 (s, 2H), 3.92-3.72 (m, 4H), 3.60-3.38 (m,4H); MS [M+H]⁺=580.0; LCMS RT=3.04 min.

Example 154N-{4-[4-amino-6-chloro-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared using the procedure to make Example 152by substituting Intermediate AAN(1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea)for Intermediate F. ¹H-NMR (CD₃OD-d₄) δ 8.62 (d, J=8 Hz, 1H), 8.06 (s,1H), 7.69-7.66 (m, 2H), 7.46-7.43 (m, 2H), 7.36-7.34 (m, 2H), 4.02 (s,2H), 4.15-3.72 (m, 4H), 3.58-3.42 (m, 4H); MS [M+H]⁺=564.0; LCMS RT=2.72min.

Example 155N-{4-[4-amino-6-chloro-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

The title compound was prepared using the procedure to make Example 152by substituting Intermediate AAH(1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea)for Intermediate F. ¹H-NMR (CD₃OD-d₄) δ 8.63 (d, J=8 Hz, 1H), 8.06 (s,1H), 7.94 (d, J=8.4 Hz, 1H), 7.36-7.30 (m, 4H), 4.82 (s, 2H), 4.15-3.72(m, 4H), 3.60-3.38 (m, 4H), 2.40 (s, 3H); MS [M+H]⁺=578.0; LCMS RT=3.05min.

Example 156N-{4-[4-amino-6-chloro-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

The title compound was prepared using the procedure to make Example 152by substituting Intermediate AAB for Intermediate F. ¹H-NMR (CD₃OD-d₄) δ8.66 (d, J=8.0 Hz, 1H), 8.30 (dd, J=11.6, 7.2 Hz, 1H), 8.06 (s, 1H),7.38-7.35 (m, 2H), 7.27 (dd, J=11.2, 6.8 Hz, 1H), 4.82 (s, 2H),4.15-3.72 (m, 4H), 3.60-3.40 (m, 4H); MS [M+H]⁺=600.0; LCMS RT=2.75 min.

Example 157N-{4-[4-amino-6-chloro-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea

The title compound was prepared using the procedure to make Example 152by substituting Intermediate AAO(1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[3-(trifluoromethyl)phenyl]urea)for Intermediate F. ¹H-NMR (CD₃OD-d₄) δ 8.29 (t, J=8.4 Hz, 1H), 8.05 (s,1H), 7.97 (s, 1H), 7.60 (dd, J=8.4, 1.6 Hz, 1H), 7.49 (t, J=7.6 Hz, 1H),7.34-7.30 (m, 2H), 7.25-7.24 (m, 1H), 4.82 (s, 2H), 4.15-3.72 (m, 4H),3.60-3.40 (m, 4H); MS [M+H]⁺=563.9; LCMS RT=2.64 min.

Example 158N-{4-[4-amino-6-chloro-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The title compound was prepared using the procedure to make Example 152by substituting Intermediate AAF(1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[4-(trifluoromethyl)pyridin-2-yl]urea)for Intermediate F. ¹H-NMR (CD₃OD-d₄) δ 8.51 (d, J=5.2 Hz, 1H), 8.40 (t,J=8.4 Hz, 1H), 8.06 (s, 1H), 7.67 (s, 1H), 7.36 (dd, J=11.6, 2.0 Hz,1H), 7.32-7.25 (m, 2H), 4.82 (s, 2H), 4.18-3.72 (m, 4H), 3.60-3.40 (m,4H); MS [M+H]⁺=564.9; LCMS RT=3.01 min.

Example 159N-{4-[4-amino-6-chloro-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-chloro-5-(trifluoromethyl)-phenyl]urea

The title compound was prepared using the procedure to make Example 152by substituting Intermediate AAK(1-[2-chloro-5-(trifluoromethyl)phenyl]-3-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea)for Intermediate F. ¹H-NMR (CD₃OD-d₄) δ 9.49 (s, 1H), 8.94 (d, J=4.4 Hz,1H), 8.66 (s, 1H), 8.39-8.33 (m, 1H), 8.06 (s, 1H), 7.64 (d, J=8.4 Hz,1H), 7.36-7.26 (m, 3H), 4.82 (s, 2H), 4.18-3.72 (m, 4H), 3.60-3.40 (m,4H); MS [M+H]⁺=597.9; LCMS RT=2.76 min.

Example 160N-{4-[4-amino-6-chloro-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea

The title compound was prepared using the procedure to make Example 152by substituting Intermediate AAP(1-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[3-(trifluoromethyl)phenyl]urea)for Intermediate F. ¹H-NMR (CD₃OD-d₄) δ 8.35 (d, J=8.4 Hz, 1H), 8.06 (s,1H), 7.99 (s, 1H), 7.64-7.61 (m, 1H), 7.58 (d, J=1.6 Hz, 1H), 7.50 (t,J=7.6 Hz, 1H), 7.41 (dd, J=8.4, 2.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H),4.82 (s, 2H), 4.18-3.72 (m, 4H), 3.60-3.40 (m, 4H); MS [M+H]⁺=579.9;LCMS RT=2.71 min.

Example 161N-{4-[4-amino-6-chloro-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(2-fluoro-5-methylphenyl)urea

The title compound was prepared using the procedure to make Example 152by substituting Intermediate AAJ(1-(2-fluoro-5-methylphenyl)-3-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea)for Intermediate F. ¹H-NMR (CD₃OD-d₄) δ 8.35 (t, J=8.4 Hz, 1H), 8.09 (s,1H), 7.94 (dd, J=7.6, 2.4 Hz, 1H), 7.32 (dd, J=11.6, 2.0 Hz, 1H),7.27-7.23 (m, 1H), 7.00 (dd, J=11.2, 8.4 Hz, 1H), 6.86-6.82 (m, 1H);4.82 (s, 2H), 4.18-3.72 (m, 4H), 3.60-3.40 (m, 4H), 2.31 (s, 3H); MS[M+H]⁺=528.0; LCMS RT=2.66 min.

Example 1621-{4-[4-amino-6-(methoxymethyl)-7-(4-methylmorpholin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-3-[2-fluoro-5-(trifluoromethyl)-phenyl]ureahydrochloride

A solution of Intermediate AB(N-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea)(200 mg, 0.42 mmol) and 4-methyl-3,6-dihydro-2H-1,4-oxazin-4-iumchloride (69 mg, 0.51 mmol) in DMF (5 mL) is allowed to stir for 1 h atrt. Volatiles are removed in vacuo, and the residue triturated withCH₂Cl₂, providing the desired compound.

Biological Evaluation

The utility of the compounds of the present invention can beillustrated, for example, by their activity in vitro in the in vitrotumor cell proliferation assay described below. The link betweenactivity in tumor cell proliferation assays in vitro and anti-tumoractivity in the clinical setting has been very well established in theart. For example, the therapeutic utility of taxol (Silvestrini et al.Stem Cells 1993, 11 (6), 528-35), taxotere (Bissery et al. Anti CancerDrugs 1995, 6 (3), 339), and topoisomerase inhibitors (Edelman et al.Cancer Chemother. Pharmacol. 1996, 37 (5), 385-93) were demonstratedwith the use of in vitro tumor proliferation assays.

Demonstration of the activity of the compounds of the present inventionmay be accomplished through in vitro, ex vivo, and in vivo assays thatare well known in the art. For example, to demonstrate the activity ofthe compounds of the present invention, the following assays may beused.

FGFR-1 TR-FRET Biochemical Assay

The FGFR-1 Assay was performed on half well 96-well opaque plates(Costar 3915) in a LANCE format. LANCE is a homogenous time resolvedfluormetry based application available through Perkin Elmer. For thisassay, 50 uL reactions were set up using: 0.6 uM ATP (Sigma), 25 nM polyGT-biotin (CIS BIO International), 2 nM Eu-labelled phospho-Tyr Ab (PY20PerkinElmer), 10 nM Streptavidin-APC (Perkin Elmer), 5 nM FGFR1-GST(generated by DRT, Bayer Healthcare), 1% DMSO, 50 mM HEPES pH 7.5, 10 mMMgCl₂, 0.1 mM EDTA, 0.015% Brij, 0.1 mg/ml BSA, 0.1% B-mercaptoethanol.All reactions were initiated with the addition of enzyme and were leftto incubate for one hour at room temperature. Time-resolved fluorescencewas then read on a Perkin Elmer VictorV Multilabel counter. The readingprotocol uses an excitation wavelength at 340 nm and emission reads atboth 615 and 665 nm. Signal was calculated as a ratio: (Fluorescence at665 nm/Fluorescence at 615 nM)*10000 for each well. The backgroundcontrol used for this assay is the signal produced with all assaycomponents excluding ATP. For IC₅₀ generation, compounds were addedprior to the enzyme initiation. A 50-fold stock plate was made withcompounds serially diluted 1:5 in a 50% DMSO/50% dH2O solution. A 1 μLaddition of the stock to the assay wells gave final compoundconcentrations ranging from 10 μM −0.128 nM in 1% DMSO. The data wereexpressed as percent inhibition: % inhibition=100−((Signal withinhibitor-background)/(Signal without inhibitor−background))*100.

Tumor Cell Proliferation

Human tumor cells (e.g., HCT116 or MDA-MB-231 cells), were seeded in aCostar 96-well plate at 3.0×10³ cells/well and grown in 150 μl of RPMIcomplete media (Invitrogen Corporation, Grand Island, N.Y.) containing10% fetal bovine serum (Hyclone, Logan, Utah) at 37° C. for 16 h in anincubator with 5% CO₂. To each well, 50 μl of additional growth mediacontaining 40 μM to 18 nM concentrations of compound with 0.4% DMSO wasadded. Cells were grown for another 72 h at 37° C. with 5% CO₂. 20 μl ofAlamar Blue (Trek Diagnostic Systems, Inc., Cleveland, Ohio) reagent wasadded to each well and incubated for 3 h at 37° C. Plates were read in aSpectraMax Gemini (Molecular Devices, CA) with 544 nm excitation and 590nm emission wavelength. IC₅₀ values were determined by linear regressionanalysis of log drug concentration versus percent inhibition.

p-Histone3

Compounds were assayed for the inhibition of histone 3 phosphorylationin colon carcinoma (HCT116). Briefly, 20,000 cells/well were seeded in a96-well black-walled, poly-d-lysine plates in RPMI+10% FBS and incubatedat 37° C. in 5% CO₂ overnight. The following day, the cells were treatedwith compounds for 24 hours at 37° C. Following compound treatment;plates were centrifuged at 1000 rpm for 2 minutes and washed twice with100 μl of cold sterile TBS. Cells were then fixed with cold 3.7%formaldehyde in TBS (4° C. for 1 hour) and then permeabalized with 0.1%Triton-X-100 in TBS (room temperature for 30 minutes). Plates were thenwashed with of 0.25% BSA-TBS and blocked with BSA solution for 1 hour atroom temperature while shaking. The supernatant was removed and replacedwith diluted primary antibody (anti-phospho-histone 3, serine 10, CellSignaling) at 1:250 in 0.25% BSA-TBS and incubated overnight at 4° C.The plates were washed and treated with diluted secondary antibody(anti-rabbit Eu-labeled) at 1:10000 in 0.25% BSA-TBS (room temperaturefor 1 hour). The antibody solution was removed from each well and washedeight times. The wash buffer was replaced with 50 μl pre-warmedenhancement solution and mixed on the orbital shaker for 10 minutes.Fluorescence was detected with a Victor V Fluorescence Detector. Thedata are expressed as percent inhibition: % inhibition=100−((Signal withinhibitor-background)/(Signal without inhibitor-background))×100.

In vivo Efficacy Studies: Staged Human Xenograft Models

Staged human xenograft models grown in mice or rats were used toevaluate compound efficacy. To generate tumors, cells harvested frommid-log phase cultures or tumor fragments from in vivo passage wereinjected s.c. in the flank of athymic mice or rats. Treatmentadministered p.o. or i.v. was initiated when all mice in each experimenthad established tumors. The general health of animals was monitored andmortality was recorded daily. Tumor dimensions and body weights wererecorded two to three times a week starting with the first day oftreatment. Tumor weights were calculated using the equation (l×w2)/2,where l and w refer to the larger and smaller dimensions collected ateach measurement. Anti-tumor efficacy was measured as tumor growthinhibition (TGI). TGI is calculated by the equation [1−(T/C)*100], whereT and C represent the mean tumor size of the treated (T) and untreatedor vehicle control (C) groups, respectively, at the end of treatment.

In vitro Soft Agar Assays Measuring Anchorage-Independent Growth:

One of the hallmarks of an oncogenically-transformed cell is its abilityto survive and proliferate in an anchorage-independent manner. Tomeasure this anchorage-independent growth, soft agar assays areperformed. A mixture of 1000 cells in 100 μl of growth medium containing0.36% agarose (supplemented with 10% (v/v) FBS) is plated onto 50 μl ofsolidified growth medium containing 0.6% (w/v) agarose in 96 wellplates. Once the cell/medium/agarose mixture have solidified, 50 μl ofgrowth medium is added to cover the wells and plates are incubatedovernight at 37° C. in a 5% CO₂ incubator. The following day, compoundsdiluted in growth media with a final concentration of DMSO not to exceed0.1% (v/v) are added to each well. Cells are further incubated for 5days at 37° C. in a humidified incubator containing 5% CO₂. On day 5, 40μl of MTS reagent (CellTiter 96 Aqueous One Solution, Promega, Madison,Wis.) is added to each well and the plates are incubated for anadditional 2 hours at 37° C. Plates are then read at 490 nm on aSpectraMax 250 plate reader (Molecular Devices, Sunnyvale, Calif.).

Percent inhibition is calculated using the following equation:% inhibition=1−(T _(5test) −T ₀)/(T _(5control) −T ₀)×100.

-   T_(5test)=O.D. at 490 nm in the presence of test compound at day 5-   T_(5control)=O.D. at 490 nm in the DMSO treated control cells at day    5-   T₀=O.D. at 490 nm in the presence of compound at day 0    Apoptosis Assays Cell Death Detection Assay to Measure DNA    Fragmentation

The Cell Death Detection ELISAPlus kit (Roche, Mannheim, Germany) isused to measure DNA fragmentation as a marker for apoptosis. Cells areseeded in 96-well plates at 10,000 cells/well and after 24 hr, are dosedand grown for an additional 48 hr in media containing 10% FBS in 5% CO₂at 37° C. Supernatants from control and treated cells are transferredinto streptavidin-coated 96-well plates and incubated with biotinylatedmouse anti-histone antibody and peroxidase-conjugated mouse anti-DNAantibody at room temperature for 2 hr. After the removal of unboundantibodies by washing, the amount of apoptosis-generated nucleosomes isquantified as the peroxidase retained in the immuno-complex using ABTS(2,2′-azino-di[3-ethylbenzthiazolin-sulfonate]) as the substrate.Absorbance is determined at 405-490 nm using a SpectraMax microplatereader (Molecular Devices, Sunnyvale, Calif.).

Apoptosis Assays: Caspase 3/7 Activation

Execution of cell death is dependent on caspase activity. Caspases 3/7are central executioners for apoptosis. Cells (10⁴ cells/well) areplated in 96-well microtiter plates and incubated in media containing10% FBS at 37° C. overnight in a humidified incubator containing 5% CO₂.On the following day, compounds are added to wells and cultures areincubated for an additional 24 hrs. Caspase 3/7 activity is measured byadding the profluorescent substrate, Z-DEVD-AFC(7-Amino-4-Trifluorocoumarin; 75 μM; Calbiochemicals, San Diego,Calif.), freezing the plate, and then thawing the cells for 3 hours atroom temperature. Plates are read at 400 nm (excitation wavelength) and505 nm (emission wavelength) on a SpectraMax Gemini microplate reader(Molecular Devices, Sunnyvale, Calif.).

Compounds of the invention were tested for activity using the FGFR1biochemical, tumor cell proliferation and p-Histone3.

Compounds of examples 9, 10, 12, 19, 26, 27, 28, 29, 31, 32, 33 44, 45,54, 58, 60, 63, 66, 68, 69, 70, 75, 79, 83, 102, 105, 111, 116, 117,119, 124, 126, 128, 131, 135, 138, 145, 154, 158, and 161 demonstrate anIC₅₀ of less than 10 nM in the FGFR-1 biochemical assay. Compounds ofexamples 1, 4, 5, 7, 13, 14, 15, 16, 20, 21, 23, 24, 34, 35, 37, 43, 47,49, 55, 57, 59, 62, 67, 74, 88, 89, 90, 96, 99, 104, 106, 109, 114, 123,140, 142, 148, 149, 152, 159, and 160 demonstrate an IC₅₀ greater than10 nM but less than 100 nM in the FGFR-1 biochemical assay. Compounds ofexamples 6, 8, 11, 40, 50, 86, 92, 94, 97, 108, 110, 150, and 156demonstrate an IC₅₀ greater than 100 nM but less than 1 μM in FGFR-1biochemical assay.

Compounds of examples 7, 12, 13, 23 and 25 demonstrate an IC₅₀ greaterthan 500 nM but less than 4 μM in the HCT116 proliferation assay.Compounds of examples 7, 12, 13 and 23 demonstrate an IC₅₀ greater than500 nM but less than 5 μM in the MDA-MB-231 proliferation assay.

Compound of examples 7, 9, 10, 13, 34, 53, 54, 69, and 111 demonstratean IC₅₀ greater than 500 nM but less than 5 μM in the p-histone3 assay.Compounds of examples 12, 20, 33, and 62 demonstrate an IC₅₀ greaterthan 5 μM but less than 10 μM in the p-histone3 assay.

It is believed that one skilled in the art, using the preceedinginformation and information available in the art, can utilize thepresent invention to its fullest extent. Those skilled in the art willrecognize that the invention may be practiced with variations on thedisclosed structures, materials, compositions and methods withoutdeparting from the spirit or scope of the invention as it is set forthherein and such variations are regarded as within the ambit of theinvention. The compounds described in the examples are intended to berepresentative of the invention, and it will be understood that thescope of the invention is not limited by the scope of the examples. Thetopic headings set forth above are meant as guidance where certaininformation can be found in the application, but are not intended to bethe only source in the application where information on such topics canbe found. All publications and patents cited above are incorporatedherein by reference.

The invention claimed is:
 1. A compound of formula (I)

wherein R¹ represents 1.1) phenyl which may optionally bear up to 4substituents independently selected from the group consisting of 1.1.a)(C₁-C₄)alkyl, which may optionally bear up to 3 substituentsindependently selected from  1.1.a1) halogen; and 1.1.c) OR¹⁰ wherein R¹⁰ represents (C₁-C₄)alkyl which may optionally bear up to 3substituents independently selected from  1.1.c1) halogen; or R¹represents 1.2) pyridine optionally bearing up to 4 substituentsindependently selected from the group consisting of 1,2.a) (C₁-C₄)alkyl,which may optionally bear up to 3 substituents independently selectedfrom  1.2.a1) halogen; R² represents hydrogen; halogen; or—(C₁-C₅)alkyl; R³ represents 3.1) —(C₁-C₅)alkyl which is optionallysubstituted with 3.1.a) -halogen; 3.1.d) —CN; 3.1.e) —OR⁸³ wherein R⁸³represents H or —(C₁-C₃)alkyl; 3.1.f) —(C₃-C₅)cycloalkyl; or 3.1.g)—NR⁸⁹R⁹⁰ wherein  R⁸⁹ represents H or —(C₁-C₃)alkyl; and  R⁹⁰ representsH or —(C₁-C₄)alkyl which is optionally substituted with 3.1.g5) —OR⁹¹wherein R⁹¹ represents H or (C₁-C₃)alkyl which may optionally bearhalogen; 3.2)

wherein R⁹⁶ represents 3.2.a) H, 3.2.b) —(C₃-C₅)cycloalkyl; or 3.2.c)—(C₁-C₅)alkyl; 3.3)

wherein R¹⁰¹ represents H or —(C₁-C₅)alkyl which may optionally bear upto 3 substituents independently selected from 3.3.a) halogen; 3.4)

wherein R¹⁰² represents H or —(C₁-C₃)alkyl which may optionally bearhalogen; and R¹⁰³ represents H or —(C₁-C₅)alkyl which may optionallybear up to 3 substituents independently selected from  3.4.a) halogen;3.6) a 5-6 membered heteroaromatic containing up to two heteroatomsselected from O, S, and N; 3.7) halogen; 3.8) —CN; or 3.9) —CH═N—OR¹⁰⁸wherein R¹⁰⁸ represents H or —C(O)—(C₁-C₃)alkyl; R⁴ represents 4.1)—(C₁-C₅)alkyl which is optionally substituted with 4.1.c) —OR¹¹⁰ whereinR¹¹⁰ represents H or —(C₁-C₃); 4.1.d) —NR¹¹⁵R¹¹⁶ wherein  R¹¹⁵represents H or —(C₁-C₃)alkyl which may optionally bear halogen and R¹¹⁶ represents H, optionally substituted phenyl, or —(C₁-C₅)alkylwhich may optionally bear up to 3 substituents independently selectedfrom 4.1.d1) halogen; and 4.1.d3) OR¹¹⁷ wherein R¹¹⁷ represents H or(C₁-C₃)alkyl which may optionally bear halogen; 4.2)

wherein R¹²¹ represents halogen or —(C₁-C₃)alkyl which may optionallybear halogen or —OR¹²² in which R¹²² represents H or —(C₁-C₃)alkyl; drepresents 1, 2, or 3; e represents 0 or 1; f represents 0, 1, or 2;4.3)

wherein R¹²³ represents —(C₁-C₃)alkyl which may optionally bear halogenor —OR¹²⁴ in which R¹²⁴ represents H or —(C₁-C₃)alkyl; g represents 1,2, or 3; h represents 0, 1, or 2; 4.4)

wherein R¹²⁵ represents  4.4.a) H;  4.4.b) —(C₁-C₃)alkyl which mayoptionally bear halogen or —OR¹²⁶ in which R¹²⁶ represents H or—(C₁-C₃)alkyl which in turn is optionally substituted with halogen; 4.4.c) —SO₂R¹²⁷ wherein R¹²⁷ represents —(C₁-C₃)alkyl which mayoptionally bear halogen;  4.4.d) —C(O)R¹²⁹ wherein R¹²⁹ represents4.4.d2) —(C₁-C₃)alkyl which may optionally bear up to 3 substituentsindependently selected from  4.4.d2.1) halogen; 4.4.5)

wherein X represents C or N; R¹³⁸ represents 4.5.a) (C₁-C₄)alkyl, whichmay optionally bear up to 3 substituents independently selected from 4.5.a1) halogen; and k represents 0, 1, or 2; 4.6)

wherein R¹⁷⁷ represents H or —(C₁-C₃)alkyl; and m represents 1, 2, or 3;4.7)

wherein n represents 1, 2, or 3; and P represents 0, 1, or 2; 4.8)

wherein q represents 1, 2, or 3; 4.9)

wherein R¹⁷⁸ represents  4.9.a) H; r represents 0, 1, or 2; and srepresents 0 or 1; 4.10)

wherein R¹⁹¹ represents  4.10.b) —(C₁-C₃)alkyl; X represents O; and trepresents 0, 1, or 2; 4.11) halogen; or 4.12) CN; or a pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1 wherein in formula(I)

R¹ represents 1.1) phenyl which may optionally bear up to 4 substituentsindependently selected from the group consisting of 1.1.a) (C₁-C₄)alkyl,which may optionally bear up to 3 substituents independently selectedfrom  1.1.a1) halogen; and 1.1.c) OR¹⁰ wherein  R¹⁰ represents H;phenyl; benzyl; (C₃-C₆)cycloalkyl; or (C₁-C₄)alkyl which may optionallybear up to 3 substituents independently selected from  1.1.c1) halogen;or R¹ represents 1.2) pyridine optionally bearing up to 4 substituentsindependently selected from the group consisting of 1.2.a) (C₁-C₄)alkyl,which may optionally bear up to 3 substituents independently selectedfrom  1.2.a 1) halogen; R² represents hydrogen; halogen; or—(C₁-C₅)alkyl; R³ represents 3.1) —(C₁-C₅)alkyl which is optionallysubstituted with 3.1.a) -halogen; 3.1.d) —CN,  3.1.e) —OR⁸³ wherein R⁸³represents H or —(C₁-C₃)alkyl, 3.1.f) —(C₃-C₅)cycloalkyl; or 3.1.g)—NR⁸⁹R⁹⁰ wherein  R⁸⁹ represents H or —(C₁-C₃)alkyl; and  R⁹⁰ representsH or —(C₁-C₄)alkyl which is optionally substituted with 3.1.g5) —OR⁹¹wherein R⁹¹ represents H or (C₁-C₃)alkyl which may optionally bearhalogen; 3.2)

wherein R⁹⁶ represents 3.2.a) H, 3.2.b) —(C₃-C₅)cycloalkyl; or  3.2.c)—(C₁-C₅)alkyl; 3.3)

wherein R¹⁰¹ represents H or —(C₁-C₅)alkyl which may optionally bear upto 3 substituents independently selected from 3.3.a) halogen; 3.4)

wherein R¹⁰² represents H or —(C₁-C₃)alkyl which may optionally bearhalogen; and R¹⁰³ represents H or —(C₁-C₅)alkyl which may optionallybear up to 3 substituents independently selected from  3.4.a) halogen;3.6) a 5-6 membered heteroaromatic containing up to two heteroatomsselected from O, S, and N; 3.7) halogen; or 3.8) —CN; R⁴ represents 4.1)—(C₁-C₅)alkyl which is optionally substituted with 4.1.c) —OR¹¹⁰ whereinR¹¹⁰ represents H or —(C₁-C₃)alkyl; 4.1.d) —NR¹¹⁵R¹¹⁶ wherein  R¹¹⁵represents H or —(C₁-C₃)alkyl which may optionally bear halogen and R¹¹⁶ represents H, optionally substituted phenyl, or —(C₁-C₅)alkylwhich may optionally bear up to 3 substituents independently selectedfrom 4.1.d1) halogen; and 4.1.d3) OR¹¹⁷ wherein R¹¹⁷ represents H or(C₁-C₃)alkyl which may optionally bear halogen; 4.2)

wherein R¹²¹ represents —(C₁-C₃)alkyl which may optionally bear halogenor —OR¹²² in which R¹²² represents H or —(C₁-C₃)alkyl; d represents 1,2, or 3; e represents 0 or 1; f represents 0, 1, or 2; 4.3)

wherein R¹²³ represents —(C₁-C₃)alkyl which may optionally bear halogenor —OR¹²⁴ in which R¹²⁴ represents H or —(C₁-C₃)alkyl; g represents 1,2, or 3; h represents 0, 1, or 2; 4.4)

wherein R¹²⁵ represents  4.4.a) H;  4.4.b) —(C₁-C₃)alkyl which mayoptionally bear halogen or —OR¹²⁶ in which R¹²⁶ represents H or—(C₁-C₃)alkyl which in turn is optionally substituted with halogen; 4.4.c) —SO₂R¹²⁷ wherein R¹²⁷ represents optionally substituted phenyl,or —(C₁-C₃)alkyl which may optionally bear halogen or OR¹²⁸ wherein R¹²⁸represents H or (C₁-C₃)alkyl;  4.4.d) —C(O)R¹²⁹ wherein R¹²⁹ represents4.4.d2) —(C₁-C₃)alkyl which may optionally bear up to 3 substituentsindependently selected from  4.4.d2.1) halogen; and  j represents 1, 2,or 3; 4.5)

wherein X represents C or N; R¹³⁸ represents 4.5.a) (C₁-C₄)alkyl, whichmay optionally bear up to 3 substituents independently selected from 4.5.a1) halogen; and k represents 0, 1, or 2; 4.6)

wherein R¹⁷⁷ represents H or —(C₁-C₃)alkyl; and m represents 1, 2, or 3;4.7)

wherein n represents 1, 2, or 3; and P represents 0, 1, or 2; 4.8)

wherein q represents 1, 2, or 3; 4.9)

wherein R¹⁷⁸ represents  4.9.a) H; r represents 0, 1, or 2; and srepresents 0 or 1; 4.10)

wherein R¹⁹¹ represents  4.10.b) —(C₁-C₃)alkyl; X represents O; and trepresents 0, 1, or 2; 4.11) halogen; or 4.12) —CN; or apharmaceutically acceptable salt thereof.
 3. A pharmaceuticalcomposition comprising a compound as defined in claim 1, plus apharmaceutically acceptable carrier.
 4. A method of treating breastcancer in a mammal, comprising administering to said mammal an effectiveamount of a compound as defined in claim
 1. 5. The method of claim 4wherein said mammal is a human.